A structural code for assembly specificity in GID/CTLH-type E3 ligases

Ubiquitylation – the covalent attachment of the small protein ubiquitin to target substrates – is a central post-translational modification in eukaryotes (Hershko and Ciechanover, 1998). Depending on chain type, length, and topology, ubiquitylation can signal for proteasomal degradation, alter subcellular localization, or regulate protein interactions (Komander and Rape, 2012). Specificity is conferred by E3 ligases, which recruit ubiquitin-loaded E2 enzymes (Zheng and Shabek, 2017). Most E3s belong to the RING family, where the RING domain directly binds the E2~ubiquitin conjugate (‘~’ denotes a thioester link between a cysteine in the E2 and the C-terminal glycine of ubiquitin), while separate regions of the ligase mediate substrate recognition (Deshaies and Joazeiro, 2009).

The GID/CTLH-type RING ligases form a conserved family of multi-subunit assemblies that share a common architectural framework but vary in composition across species. In yeast, this ligase is known as the GID (glucose-induced-deficient) complex, whereas in mammals, it is referred to as the CTLH (C-terminal to LisH) complex; functionally, both represent variations of the same underlying E3 platform (Alpi et al., 2025).

A defining feature of this ligase family is its use of the dedicated E2 enzyme Ube2H, which exemplifies a remarkably specific and evolutionarily conserved E2-E3 pairing (Chen et al., 2017; Chrustowicz et al., 2024; Regelmann et al., 2003; Sherpa et al., 2022; Zavortink et al., 2020). Ube2H engages the RING domain through the canonical E2-E3 interface but is further stabilized by an additional phosphorylation-dependent interface (Chrustowicz et al., 2024).

Even more exceptional is the structural organization of the CTLH complex. Each core subunit contains a LisH (lissencephaly-1 homology) motif (Emes and Ponting, 2001), an eponymous CTLH (Kobayashi et al., 2007) motif, and a CRA (CT-11-RanBPM) (Menon et al., 2004) motif (Figure 1A). The CRA motif is bipartite: the N-terminal segment (CRA^N) folds together with the CTLH motif to form a helical CTLH-CRA^N domain, whereas the C-terminal helix (CRA^C) bends toward the LisH motif and stabilizes the LisH-mediated dimer through additional interactions (Qiao et al., 2020; Figure 1B). Through alternating dimers of LisH-CRA^C and CTLH-CRA^N domains, the complex assembles into a characteristic ring-shaped scaffold (Figure 1C) of exceptional size (>1 MDa) (Chrustowicz et al., 2024; Mohamed et al., 2021; Sherpa et al., 2021).

Figure 1 with 3 supplements see all

Download asset Open asset

Outside the CTLH complex, the LisH-CTLH-CRA architecture occurs only sporadically and has been structurally confirmed in a few cases: the human splicing protein SMU1 (Ashraf et al., 2019), the mouse microtubule-associated protein Wdr47 (Ren et al., 2022), and the plant transcriptional co-repressors TOPLESS and TOPLESS-related protein 2 (TPR2) (Ke et al., 2015; Ma et al., 2017; Martin-Arevalillo et al., 2017). In these proteins, only the LisH and CTLH motifs are sequence-annotated, while the CRA-like region is inferred from the shared fold. As this architecture is rare elsewhere, the high density of LisH-CTLH-CRA modules within the CTLH complex is especially striking. To date, no other multi-subunit complex – E3 ligase or otherwise – has been shown to use this architecture to assemble.

Comparative genomics show that versions of the CTLH complex core proteins (Rmnd5, Maea, Twa1, RanBP9, and Wdr26) were already present in the last eukaryotic common ancestor, implying that the CTLH scaffold emerged early in eukaryotic evolution (Francis et al., 2013; Tomaštíková et al., 2012). Subsequent duplications diversified the complex further and allowed alternative assemblies – e.g., Rmnd5 split into A and B paralogs, and RanBP9 duplicated to RanBP10. By contrast, muskelin appears metazoan-specific, representing a later innovation that expanded function without altering the underlying scaffold (Francis et al., 2013).

Overall, the ring-shaped scaffold comprises eight LisH-CRA^C interactions interlinked by eight CTLH-CRA^N contacts (Figure 1C). The three distinct LisH-CRA^C dimers are: (i) the RING pair Rmnd5a-Maea (further stabilized by their coiled-coil segments; Chrustowicz et al., 2024), (ii) RanBP9/10-Twa1, and (iii) homodimers of Wdr26 or muskelin (note: muskelin dimerizes via LisH only [Barbulescu et al., 2024; Delto et al., 2015], lacking a CRA^C helix). The two CTLH-CRA^N links are: (i) Twa1 with Maea or Rmnd5a and (ii) RanBP9/10 with Wdr26 or muskelin. Together, two Rmnd5a-Maea dimers connect via four RanBP9/10-Twa1 dimers to two Wdr26 or muskelin homodimers, forming a platform for substrates and receptors positioned at the ring’s center (Figure 1A; Qiao et al., 2020; Sherpa et al., 2021; Mohamed et al., 2021; Lampert et al., 2018; van gen Hassend et al., 2023; Gottemukkala et al., 2024).

Substrates bind either directly to the core (e.g. through muskelin or Wdr26) or via dedicated receptors (such as Gid4, Ypel5 [Gottemukkala et al., 2024], or FAM72A [Barbulescu et al., 2024; Feng et al., 2025]), or a combination of both. Gid4 tethers to adaptor protein Armc8, which in turn is anchored by Twa1 (Qiao et al., 2020; Sherpa et al., 2022; van gen Hassend et al., 2023); Ypel5 binds the WD40 domain of Wdr26, and FAM72A engages muskelin’s discoidin and kelch domains (Barbulescu et al., 2024; Figure 1C). In essence, a modular, variable core combined with interchangeable substrate receptors creates a combinatorial platform that broadens substrate recognition across diverse pathways, including metabolic regulation (Gottemukkala et al., 2024; Leal-Esteban et al., 2018; Pham et al., 2025; Yi et al., 2024), modulation of bacterial growth (Simwela et al., 2024), cancer development (Amin et al., 2015; Fan et al., 2014; Huffman et al., 2019; Jiang et al., 2015; Orlacchio et al., 2025; Sun et al., 2021), aging (Liu et al., 2020), DNA repair (Barbulescu et al., 2024; Palmieri et al., 2018), erythroid maturation (Soni et al., 2008; Zhen et al., 2020; Sherpa et al., 2022), B-cell development (Barbulescu et al., 2025), and other developmental processes such as early embryogenesis (maternal-to-zygotic transition [Briney et al., 2025; Cao et al., 2020; Zavortink et al., 2020]) and neurodevelopment (Gross et al., 2024; Hantel et al., 2022; Lu et al., 2017; Palavicini et al., 2013; Pfirrmann et al., 2015; Skraban et al., 2017; Zeinali et al., 2025).

So far, only a limited set of substrates has been mapped to their recognition route, and the repertoire diverges between species. In yeast, Gid4 recognizes gluconeogenic enzymes (Fbp1, Icl1, Mdh2, Pck1) via their N-terminal proline (Pro/N-end rule) (Chen et al., 2021; Chen et al., 2017; Hämmerle et al., 1998; Regelmann et al., 2003). In mammals, the CTLH complex does not target these enzymes; instead, it ubiquitylates the Gid4-dependent receptor-signaling protein ZMYND19 (Mohamed et al., 2021) and the Rho-GTPase activator ARHGAP11A (Bagci et al., 2024) but without an N-terminal Pro requirement. Additional examples include the base excision repair protein UNG2 (Barbulescu et al., 2024) via FAM72A, the metabolic protein NMNAT1 (Gottemukkala et al., 2024) and the transcriptional regulator HBP1 (Lampert et al., 2018; Mohamed et al., 2021) via Wdr26, and the mevalonate pathway protein HMGCS1 (Maitland et al., 2024; Owens et al., 2024; Yi et al., 2024) via muskelin and Gid4 (Pro-dependent).

Despite substantial progress, high-resolution structural coverage of the mammalian CTLH complex and its substrates remains limited. Existing cryo-EM reconstructions define the overall architecture but lack atomic detail for several regions – most notably the CTLH-CRA^N domains (Figure 1C). Consequently, key aspects of assembly and specificity have remained unresolved. Moreover, most available structures contain RanBP9; incorporation of RanBP10 is presumed to be similar based on a low-resolution cryo-EM map (Sherpa et al., 2022), but has not yet been characterized in detail.

To close this gap, we determined crystal structures of several mammalian CTLH complex components: the RanBP10-Twa1 heterodimer, and the CTLH-CRA^N domains of RanBP9, RanBP10, Maea, Twa1, and the RanBP9-muskelin complex. Guided by these structures, we combined targeted mutagenesis with quantitative binding assays to map residues governing partner specificity and to reprogram pairing preferences. We engineered RanBP10 variants that switch binding preference from muskelin to Maea, and Twa1 variants that switch from Maea to muskelin. We also determined structures of a RanBP10 specificity-switch mutant alone and in complex with Maea, as well as a Twa1 mutant bound to Maea. Together, these results define a CTLH-CRA^N specificity code, illustrating the evolutionary diversification of this unique type of E3 ligase scaffold. This engineering toolkit might be used in future studies for the controlled assembly of alternative ring compositions, thus enabling analysis of substrate dependencies or the design entirely new protein ring assemblies.

How do you build a megadalton protein ring? The CTLH complex achieves this with helical scaffold proteins that have two distinct dimerization interfaces. Both interfaces – the LisH domain (Delto et al., 2015; Emes and Ponting, 2001) and the CRA dimerization interface – consist of two α-helices dominated by hydrophobic residues at their core, such as leucine and phenylalanine in the LisH domain (Figure 1—figure supplement 2) or a conserved leucine in the CRA interface (Figure 6, marked with *). Specificity arises from additional interactions such as specific hydrogen bonds or π-π stacking. The geometries of these interfaces, however, differ: CRA helices align nearly parallel, so that adjacent CRA dimers contact each other almost orthogonally, whereas LisH dimers adopt an open angle of about 30°, with the second helix running almost parallel while the first crosses its partner. Additional structural elements stabilize both helix pairs: LisH dimerization is reinforced by a leucine-rich cross-over helix (CRA^C), whereas CRA dimerization is supported by a loop segment following the second helix that folds back and contributes further contacts (Chrustowicz et al., 2024; Qiao et al., 2020; Sherpa et al., 2021).

Figure 6 with 4 supplements see all

Download asset Open asset

While many ring-shaped assemblies – such as sliding clamps, ion channels, pore complexes, chaperonins, AAA+ ATPases, and even viral capsids – are formed by homooligomerization, the CTLH complex uses heterooligomerization. Although a CTLH-like geometry could, in principle, be built from a single oligomerizing subunit, such an assembly would be unsuitable for a RING E3 ligase, which must simultaneously provide adaptor interfaces for E2~Ub and recognition surfaces for substrates positioned at defined sites. Achieving this spatial choreography requires heterotypic subunits that use the same assembly principle but deploy distinct domains around the ring – allowing form to follow function.

Our crystal structures of CTLH-CRA domains provide high-resolution insights into otherwise, at least when expressed in E. coli, insoluble proteins such as RanBP9/10 and Maea. Maea homodimerization, reported here for the first time, is compatible with the full-length protein but would prevent ring formation and therefore likely represents an intermediate state in the assembly. The previously uncharacterized RanBP9-muskelin interface revealed how two CTLH-CRA domains interact. Using these structural data, we engineered CTLH-CRA domains with swapped binding specificity: A RanBP10 mutant that acquired a Twa1-like preference for Maea instead of muskelin, and Twa1 mutants that adopted a RanBP9/10-like preference for muskelin instead of Maea.

Importantly, swapping the specificity of these very tight interfaces (nM-pM range) is substantially more challenging than merely disrupting them. Charged substitutions introduced into the hydrophobic core readily abolished dimerization – e.g., the Twa1_3 mutant (L122R, A151R) no longer bound Maea (Figure 4—figure supplement 2), or the pathogenic human Wdr26 S254R variant (S234R in mouse), which causes, by impaired complex formation (Gross et al., 2024), Skraban-Deardorff syndrome (Skraban et al., 2017; Tickle et al., 2016), an intellectual disability disorder. By contrast, successful switching requires a coordinated loss of the original contacts together with the formation of new partner-specific interactions, while preserving the rather unspecific hydrophobic core architecture.

For RanBP10, relieving a single clash by substituting Q519 with glycine (R10_G) was sufficient to permit Maea binding, and in combination with F543L, Y548F, and V556F, to abolish muskelin binding (Figure 6). Both R10_G and R10_GLFF bound Maea but not Twa1, even though the Q519G substitution should also alleviate a clash with Twa1, which – like Maea – carries a phenylalanine at the equivalent position. The difference may be explained by the newly formed hydrogen bond in the R10_GLFF-Maea complex (Figure 3F), in which Maea Y254 interacts with RanBP10 Q540, whereas Twa1 F160 cannot. Together with additional subtle steric constraints, this likely accounts for the Maea specificity of R10_GLFF.

In contrast, reversing the specificity in Twa1 required more extensive remodeling – eight rather than four substitutions (Figure 6) – reflecting differences in overall geometry, such as the kink in the first CRA helix and the absence of pre-existing residues that could engage directly in the new interactions, like RanBP10 Q540. Engineered Twa1_52 mutant bound (near) full-length muskelin and Wdr26 comparably but was outcompeted by its native partners RanBP9 and RanBP10. Interestingly, RanBP9 appears to bind Wdr26 approximately tenfold weaker than RanBP10, possibly explaining why RanBP10 can substitute for RanBP9 in Wdr26-containing CTLH complexes during erythrocyte maturation (Sherpa et al., 2022), although the functional significance of this remains unclear. Despite this difference, both proteins likely assemble similarly owing to their nearly identical interfaces.

AlphaFold3 predictions (Abramson et al., 2024) of CTLH-CRA dimerization interfaces across model organisms indicate that the determinants of binding specificity are broadly conserved beyond mammals (Figure 6—figure supplement 1). In muskelin-containing species such as X. laevis and D. rerio, the RanBP9/10 interface is particularly well preserved, employing the same mechanism of specificity as in mouse: π–π and Met–π interactions involving RanBP9/10 phenylalanine residues, and a hydrogen bond formed by RanBP9/10 tyrosine with muskelin glutamine or Wdr26 histidine. Remarkably, this hydrogen bond is conserved even between the A. thaliana homologs of RanBP9 and Wdr26.

By contrast, C. elegans Wdr26 contains an insertion at the interface predicted to form β-strands, resulting in an AlphaFold3 prediction with low interface confidence. In yeast, the Gid1 (RanBP9 homologue) interface is largely conserved, except for the missing phenylalanine (Figure 6—figure supplement 2; PDB: 7NSB). The Gid1 N-terminus, however, forms an additional contact site with the Wdr26 homolog Gid7, a secondary interaction that likely relaxed or shifted the constraints governing interface specificity.

Core-specific determinants, such as the conserved leucine residue (*), are also present in other CTLH-CRA domains such as SMU1, Wdr47, TOPLESS, and TRP2 (Figure 6—figure supplement 3A). However, the position of a conserved aromatic residue distinguishes different interface classes (Figure 6—figure supplement 3B). Muskelin uses its phenylalanine, immediately following the conserved leucine*, for π-π stacking with RanBP9, whereas other CTLH complex members carry their conserved Phe/Tyr two residues after the leucine*. This aromatic residue is crucial for specific interactions – e.g., Maea F245 not only discriminates against RanBP9/10 binding but also stabilizes the loop that folds back to form a hydrogen bond with Y254. By contrast, non-CTLH complex CTLH-CRA domains have their aromatic residue shifted seven positions upstream to leucine*, resulting in a loop that does not fold back into the interface. A comparison of the Maea and TRP2 homodimerization interfaces (Figure 6—figure supplement 3B) showed that this positional shift relocates the aromatic residue to the opposite side of the interface, reflecting positional rather than sequence conservation.

Within the CTLH complex subunits, LisH-CRA^C and CTLH-CRA domains exclusively mediate ring assembly – except for Twa1. Twa1 can additionally interact via its CTLH-CRA domain with Armc8 through electrostatic complementarity, i.e., the negatively charged surface of Twa1 (Figure 6—figure supplement 4) engages positively charged patches on Armc8 (Sherpa et al., 2021). Outside the CTLH complex, CTLH-CRA domains have hydrophobic grooves adjacent to the dimerization interface that mediate protein interactions (Figure 6—figure supplement 3C). For example, SMU1 binds RED on the N-terminal side of the interface (Ashraf et al., 2019), whereas TRP2 binds IAA1, NINJA, and EAR-motif peptides on the C-terminal side (Ke et al., 2015). These observations suggest that such binding grooves are either absent in CTLH complex subunits or may represent an underexplored protein interaction site (Figure 6—figure supplement 4), potentially explaining structural differences of the RanBP9 and RanBP10 paralogs which behave similarly in the assembly.

The CTLH complex exemplifies how evolution can elaborate a simple helical scaffold into a versatile assembly platform. Subtle variations in aromatic and polar residues fine-tune partner specificity, giving rise to distinct LisH-CRA^C and CTLH-CRA interfaces. By mapping this residue-level code and demonstrating bidirectional specificity rewiring of CTLH-CRA domains, we provide a framework for understanding and rationally manipulating CTLH complex ring assembly.

Mutations such as R10_LFF or Twa1_3, which selectively disrupt CRA-CRA dimerization, provide powerful tools to dissect assembly-dependent functions. Unlike protein depletion or knockout strategies, targeted interface mutations selectively perturb defined subunit interactions while preserving other structural or regulatory roles. While R10_LFF blocks the specificity determinants identified in this manuscript, the conserved nature of the CRA interface, exemplified by Twa1_3 (L122R, A151R), suggests a broader strategy. Substitution of analogous hydrophobic residues with charged residues (see alignment, Figure 2B) in other core CTLH subunits would be expected to disrupt CRA-mediated interactions in a similar manner.

Such mutations allow selective enforcement of defined assembly routes by disabling alternative ring-forming interactions. For example, mutation of key residues within the muskelin CRA interface (e.g. specificity residues F686 and Q679; Figure 2) would prevent muskelin incorporation into the ring, thereby favoring substitution by Wdr26 during assembly. Conversely, mutation of the Wdr26 CRA interface would promote incorporation of muskelin. Combining these CRA-interface mutations with interaction-blocking variants such as R10_LFF would further restrict alternative connectivity and enable generation of ring complexes with defined composition, such as RanBP9-Wdr26 assemblies.

Specificity-switch mutations extend this approach by enabling non-canonical CTLH ring architectures. Introduction of the Twa1_52 mutant may favor incorporation of Wdr26/muskelin dimers at the expense of Rmnd5a-Maea, thus resulting in assemblies lacking catalytic modules. Conversely, the R10_GLFF mutation may promote incorporation of additional catalytic modules by replacing Wdr26/muskelin dimers. Such complexes would lack Wdr26/muskelin-mediated substrate recruitment and may therefore rely more strongly on the Gid4-Armc8 recognition route. When both switching mutations are combined, the orientation of the RanBP9/10-Twa1 module within the ring may be inverted, potentially altering the spatial positioning of domains such as the RanBP9/10 SPRY domain and thereby influencing substrate engagement via the Gid4-Armc8 axis.

Collectively, these findings define a residue-level structural code governing CTLH ring assembly and demonstrate that complex architecture can be rationally manipulated. The ability to selectively eliminate, redirect, or reorient subunit interactions may help to uncover substrate-specific dependencies and could serve as blueprints for designing other ring-shaped complexes beyond E3 ligases.

The models of the CTLH complex subunits are deposited in the Protein Data Bank with the following accession codes: 9SNE, 9SNF, 9SNG, 9SNH, 9SNI, 9SNV, 9SOH, 9SOI, and 9SOC. All other materials, e.g. primers or plasmids, are available upon request.

1. 1. van gen Hassend PM
   2. Schindelin H

   (2026) Worldwide Protein Data Bank

   CTLH-CRA domain of murine RanBP9.

   https://doi.org/10.2210/pdb9sne/pdb
2. 1. van gen Hassend PM
   2. Schindelin H

   (2026) Worldwide Protein Data Bank

   CTLH-CRA domain of murine RanBP10.

   https://doi.org/10.2210/pdb9SNF/pdb
3. 1. van gen Hassend PM
   2. Schindelin H

   (2026) Worldwide Protein Data Bank

   CTLH-CRA domain of murine RanBP10 mutant Q519G, F543L, Y548F and V556F.

   https://doi.org/10.2210/pdb9SNG/pdb
4. 1. van gen Hassend PM
   2. Schindelin H

   (2026) Worldwide Protein Data Bank

   CTLH-CRA domain of murine Maea.

   https://doi.org/10.2210/pdb9SNH/pdb
5. 1. van gen Hassend PM
   2. Schindelin H

   (2026) Worldwide Protein Data Bank

   CTLH-CRA domain of murine Twa1.

   https://doi.org/10.2210/pdb9SNI/pdb
6. 1. van gen Hassend PM
   2. Schindelin H

   (2026) Worldwide Protein Data Bank

   CTLH-CRA domains of the RanBP9-muskelin complex.

   https://doi.org/10.2210/pdb9SNV/pdb
7. 1. van gen Hassend PM
   2. Schindelin H

   (2026) Worldwide Protein Data Bank

   CTLH-CRA domains of the Maea-RanBP10 mutant (Q519G, F543L, Y548F and V556F) complex.

   https://doi.org/10.2210/pdb9SOH/pdb
8. 1. van gen Hassend PM
   2. Schindelin H

   (2026) Worldwide Protein Data Bank

   CTLH-CRA domains of Maea-Twa1 mutant (A125G, Q126R, T127del, Q128E, A130Q, M143L, E144Q, L147F, A148S, F152Y and F160V) complex.

   https://doi.org/10.2210/pdb9SOI/pdb
9. 1. van gen Hassend PM
   2. Schindelin H

   (2026) Worldwide Protein Data Bank

   Murine RanBP10-Twa1 complex.

   https://doi.org/10.2210/pdb9SOC/pdb

1. 1. Abramson J
   2. Adler J
   3. Dunger J
   4. Evans R
   5. Green T
   6. Pritzel A
   7. Ronneberger O
   8. Willmore L
   9. Ballard AJ
   10. Bambrick J
   11. Bodenstein SW
   12. Evans DA
   13. Hung C-C
   14. O’Neill M
   15. Reiman D
   16. Tunyasuvunakool K
   17. Wu Z
   18. Žemgulytė A
   19. Arvaniti E
   20. Beattie C
   21. Bertolli O
   22. Bridgland A
   23. Cherepanov A
   24. Congreve M
   25. Cowen-Rivers AI
   26. Cowie A
   27. Figurnov M
   28. Fuchs FB
   29. Gladman H
   30. Jain R
   31. Khan YA
   32. Low CMR
   33. Perlin K
   34. Potapenko A
   35. Savy P
   36. Singh S
   37. Stecula A
   38. Thillaisundaram A
   39. Tong C
   40. Yakneen S
   41. Zhong ED
   42. Zielinski M
   43. Žídek A
   44. Bapst V
   45. Kohli P
   46. Jaderberg M
   47. Hassabis D
   48. Jumper JM

   (2024) Accurate structure prediction of biomolecular interactions with AlphaFold 3

   Nature 630:493–500.

   https://doi.org/10.1038/s41586-024-07487-w

   • PubMed
   • Google Scholar
2. 1. Adams PD
   2. Afonine PV
   3. Bunkóczi G
   4. Chen VB
   5. Davis IW
   6. Echols N
   7. Headd JJ
   8. Hung LW
   9. Kapral GJ
   10. Grosse-Kunstleve RW
   11. McCoy AJ
   12. Moriarty NW
   13. Oeffner R
   14. Read RJ
   15. Richardson DC
   16. Richardson JS
   17. Terwilliger TC
   18. Zwart PH

   (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution

   Acta Crystallographica. Section D, Biological Crystallography 66:213–221.

   https://doi.org/10.1107/S0907444909052925

   • PubMed
   • Google Scholar
3. 1. Alpi AF
   2. Chrustowicz J
   3. Sherpa D
   4. Schulman BA

   (2025) The many faces of the GID/CTLH E3 ligase complex

   Biochemical Society Transactions 53:1351–1364.

   https://doi.org/10.1042/BST20253074

   • PubMed
   • Google Scholar
4. 1. Amin A
   2. Bukhari S
   3. Mokhdomi TA
   4. Anjum N
   5. Wafai AH
   6. Wani Z
   7. Manzoor S
   8. Koul AM
   9. Amin B
   10. Ain QU
   11. Qazi H
   12. Tyub S
   13. Lone GN
   14. Qadri RA

   (2015) Comparative proteomics and global genome-wide expression data implicate role of ARMC8 in lung cancer

   Asian Pacific Journal of Cancer Prevention 16:3691–3696.

   https://doi.org/10.7314/apjcp.2015.16.9.3691

   • PubMed
   • Google Scholar
5. 1. Ashraf U
   2. Tengo L
   3. Le Corre L
   4. Fournier G
   5. Busca P
   6. McCarthy AA
   7. Rameix-Welti MA
   8. Gravier-Pelletier C
   9. Ruigrok RWH
   10. Jacob Y
   11. Vidalain PO
   12. Pietrancosta N
   13. Crépin T
   14. Naffakh N

   (2019) Destabilization of the human RED–SMU1 splicing complex as a basis for host-directed antiinfluenza strategy

   PNAS 116:10968–10977.

   https://doi.org/10.1073/pnas.1901214116

   • Google Scholar
6. 1. Bagci H
   2. Winkler M
   3. Grädel B
   4. Uliana F
   5. Boulais J
   6. Mohamed WI
   7. Park SL
   8. Côté JF
   9. Pertz O
   10. Peter M

   (2024) The hGID^GID4 E3 ubiquitin ligase complex targets ARHGAP11A to regulate cell migration

   Life Science Alliance 7:e202403046.

   https://doi.org/10.26508/lsa.202403046

   • PubMed
   • Google Scholar
7. 1. Barbulescu P
   2. Chana CK
   3. Wong MK
   4. Ben Makhlouf I
   5. Bruce JP
   6. Feng Y
   7. Keszei AFA
   8. Wong C
   9. Mohamad-Ramshan R
   10. McGary LC
   11. Kashem MA
   12. Ceccarelli DF
   13. Orlicky S
   14. Fang Y
   15. Kuang H
   16. Mazhab-Jafari M
   17. Pezo RC
   18. Bhagwat AS
   19. Pugh TJ
   20. Gingras AC
   21. Sicheri F
   22. Martin A

   (2024) FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation

   Nature Communications 15:7541.

   https://doi.org/10.1038/s41467-024-52009-x

   • PubMed
   • Google Scholar
8. 1. Barbulescu P
   2. Wong MK
   3. Baronian L
   4. Wang P
   5. Aderinto A
   6. Kneussel M
   7. Martin A

   (2025) MKLN1-dependent GID4/CTLH E3 ubiquitin ligase complex assemblies are required to support B-cell antibody diversification

   Journal of Immunology 214:2564–2574.

   https://doi.org/10.1093/jimmun/vkaf201

   • PubMed
   • Google Scholar
9. 1. Briney CA
   2. Henriksen JC
   3. Lin C
   4. Jones LA
   5. Benner L
   6. Rains AB
   7. Gutierrez R
   8. Gafken PR
   9. Rissland OS

   (2025) Muskelin is a substrate adaptor of the highly regulated Drosophila embryonic CTLH E3 ligase

   EMBO Reports 26:1647–1669.

   https://doi.org/10.1038/s44319-025-00397-6

   • PubMed
   • Google Scholar
10. 1. Cao WX
    2. Kabelitz S
    3. Gupta M
    4. Yeung E
    5. Lin S
    6. Rammelt C
    7. Ihling C
    8. Pekovic F
    9. Low TCH
    10. Siddiqui NU
    11. Cheng MHK
    12. Angers S
    13. Smibert CA
    14. Wühr M
    15. Wahle E
    16. Lipshitz HD

    (2020) Precise temporal regulation of post-transcriptional repressors is required for an orderly drosophila maternal-to-zygotic transition

    Cell Reports 31:107783.

    https://doi.org/10.1016/j.celrep.2020.107783

    • PubMed
    • Google Scholar
11. 1. Chen SJ
    2. Wu X
    3. Wadas B
    4. Oh JH
    5. Varshavsky A

    (2017) An N-end rule pathway that recognizes proline and destroys gluconeogenic enzymes

    Science 355:eaal3655.

    https://doi.org/10.1126/science.aal3655

    • PubMed
    • Google Scholar
12. 1. Chen SJ
    2. Kim L
    3. Song HK
    4. Varshavsky A

    (2021) Aminopeptidases trim Xaa-Pro proteins, initiating their degradation by the Pro/N-degron pathway

    PNAS 118:34663735.

    https://doi.org/10.1073/pnas.2115430118

    • Google Scholar
13. 1. Chrustowicz J
    2. Sherpa D
    3. Li J
    4. Langlois CR
    5. Papadopoulou EC
    6. Vu DT
    7. Hehl LA
    8. Karayel Ö
    9. Beier V
    10. von Gronau S
    11. Müller J
    12. Prabu JR
    13. Mann M
    14. Kleiger G
    15. Alpi AF
    16. Schulman BA

    (2024) Multisite phosphorylation dictates selective E2-E3 pairing as revealed by Ubc8/UBE2H-GID/CTLH assemblies

    Molecular Cell 84:293–308.

    https://doi.org/10.1016/j.molcel.2023.11.027

    • PubMed
    • Google Scholar
14. 1. Delto CF
    2. Heisler FF
    3. Kuper J
    4. Sander B
    5. Kneussel M
    6. Schindelin H

    (2015) The LisH motif of muskelin is crucial for oligomerization and governs intracellular localization

    Structure 23:364–373.

    https://doi.org/10.1016/j.str.2014.11.016

    • PubMed
    • Google Scholar
15. 1. Deshaies RJ
    2. Joazeiro CAP

    (2009) RING domain E3 ubiquitin ligases

    Annual Review of Biochemistry 78:399–434.

    https://doi.org/10.1146/annurev.biochem.78.101807.093809

    • PubMed
    • Google Scholar
16. 1. Emes RD
    2. Ponting CP

    (2001) A new sequence motif linking lissencephaly, Treacher Collins and oral-facial-digital type 1 syndromes, microtubule dynamics and cell migration

    Human Molecular Genetics 10:2813–2820.

    https://doi.org/10.1093/hmg/10.24.2813

    • PubMed
    • Google Scholar
17. 1. Emsley P
    2. Lohkamp B
    3. Scott WG
    4. Cowtan K

    (2010) Features and development of Coot

    Acta Crystallographica. Section D, Biological Crystallography 66:486–501.

    https://doi.org/10.1107/S0907444910007493

    • PubMed
    • Google Scholar
18. 1. Fan C
    2. Zhao Y
    3. Mao X
    4. Miao Y
    5. Lin X
    6. Jiang G
    7. Zhang X
    8. Han Q
    9. Luan L
    10. Wang E

    (2014) Armc8 expression was elevated during atypia-to-carcinoma progression and associated with cancer development of breast carcinoma

    Tumour Biology 35:11337–11343.

    https://doi.org/10.1007/s13277-014-2473-0

    • PubMed
    • Google Scholar
19. 1. Feng Y
    2. Barbulescu P
    3. Chana CK
    4. Shirdarreh M
    5. Yang H
    6. Wu L
    7. Mamand S
    8. Kashem M
    9. Zia A
    10. Han M
    11. Tsao J
    12. Pugh T
    13. Cescon D
    14. Schatz DG
    15. Sicheri F
    16. Martin A
    17. Pezo RC

    (2025) FAM72A promotes UNG2 degradation and mutagenesis in human cancer cells

    Scientific Reports 15:23467.

    https://doi.org/10.1038/s41598-025-07723-x

    • Google Scholar
20. 1. Francis O
    2. Han F
    3. Adams JC

    (2013) Molecular phylogeny of a RING E3 ubiquitin ligase, conserved in eukaryotic cells and dominated by homologous components, the muskelin/RanBPM/CTLH complex

    PLOS ONE 8:e75217.

    https://doi.org/10.1371/journal.pone.0075217

    • PubMed
    • Google Scholar
21. 1. Gottemukkala KV
    2. Chrustowicz J
    3. Sherpa D
    4. Sepic S
    5. Vu DT
    6. Karayel Ö
    7. Papadopoulou EC
    8. Gross A
    9. Schorpp K
    10. von Gronau S
    11. Hadian K
    12. Murray PJ
    13. Mann M
    14. Schulman BA
    15. Alpi AF

    (2024) Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism

    Molecular Cell 84:1948–1963.

    https://doi.org/10.1016/j.molcel.2024.04.014

    • PubMed
    • Google Scholar
22. 1. Gross A
    2. Müller J
    3. Chrustowicz J
    4. Strasser A
    5. Gottemukkala KV
    6. Sherpa D
    7. Schulman BA
    8. Murray PJ
    9. Alpi AF

    (2024) Skraban-Deardorff intellectual disability syndrome-associated mutations in WDR26 impair CTLH E3 complex assembly

    FEBS Letters 598:978–994.

    https://doi.org/10.1002/1873-3468.14866

    • PubMed
    • Google Scholar
23. 1. Hämmerle M
    2. Bauer J
    3. Rose M
    4. Szallies A
    5. Thumm M
    6. Düsterhus S
    7. Mecke D
    8. Entian KD
    9. Wolf DH

    (1998) Proteins of newly isolated mutants and the amino-terminal proline are essential for ubiquitin-proteasome-catalyzed catabolite degradation of fructose-1,6-bisphosphatase of Saccharomyces cerevisiae

    The Journal of Biological Chemistry 273:25000–25005.

    https://doi.org/10.1074/jbc.273.39.25000

    • PubMed
    • Google Scholar
24. 1. Hantel F
    2. Liu H
    3. Fechtner L
    4. Neuhaus H
    5. Ding J
    6. Arlt D
    7. Walentek P
    8. Villavicencio-Lorini P
    9. Gerhardt C
    10. Hollemann T
    11. Pfirrmann T

    (2022) Cilia-localized GID/CTLH ubiquitin ligase complex regulates protein homeostasis of sonic hedgehog signaling components

    Journal of Cell Science 135:jcs259209.

    https://doi.org/10.1242/jcs.259209

    • PubMed
    • Google Scholar
25. 1. Hershko A
    2. Ciechanover A

    (1998) The ubiquitin system

    Annual Review of Biochemistry 67:425–479.

    https://doi.org/10.1146/annurev.biochem.67.1.425

    • PubMed
    • Google Scholar
26. 1. Huffman N
    2. Palmieri D
    3. Coppola V

    (2019) The CTLH complex in cancer cell plasticity

    Journal of Oncology 2019:4216750.

    https://doi.org/10.1155/2019/4216750

    • PubMed
    • Google Scholar
27. 1. Jiang G
    2. Yang D
    3. Wang L
    4. Zhang X
    5. Xu H
    6. Miao Y
    7. Wang E
    8. Zhang Y

    (2015) A novel biomarker ARMc8 promotes the malignant progression of ovarian cancer

    Human Pathology 46:1471–1479.

    https://doi.org/10.1016/j.humpath.2015.06.004

    • PubMed
    • Google Scholar
28. 1. Jumper J
    2. Evans R
    3. Pritzel A
    4. Green T
    5. Figurnov M
    6. Ronneberger O
    7. Tunyasuvunakool K
    8. Bates R
    9. Žídek A
    10. Potapenko A
    11. Bridgland A
    12. Meyer C
    13. Kohl SAA
    14. Ballard AJ
    15. Cowie A
    16. Romera-Paredes B
    17. Nikolov S
    18. Jain R
    19. Adler J
    20. Back T
    21. Petersen S
    22. Reiman D
    23. Clancy E
    24. Zielinski M
    25. Steinegger M
    26. Pacholska M
    27. Berghammer T
    28. Bodenstein S
    29. Silver D
    30. Vinyals O
    31. Senior AW
    32. Kavukcuoglu K
    33. Kohli P
    34. Hassabis D

    (2021) Highly accurate protein structure prediction with AlphaFold

    Nature 596:583–589.

    https://doi.org/10.1038/s41586-021-03819-2

    • PubMed
    • Google Scholar
29. 1. Kabsch W

    (2010) XDS

    Acta Crystallographica. Section D, Biological Crystallography 66:125–132.

    https://doi.org/10.1107/S0907444909047337

    • PubMed
    • Google Scholar
30. 1. Ke J
    2. Ma H
    3. Gu X
    4. Thelen A
    5. Brunzelle JS
    6. Li J
    7. Xu HE
    8. Melcher K

    (2015) Structural basis for recognition of diverse transcriptional repressors by the TOPLESS family of corepressors

    Science Advances 1:e1500107.

    https://doi.org/10.1126/sciadv.1500107

    • PubMed
    • Google Scholar
31. 1. Kobayashi N
    2. Yang J
    3. Ueda A
    4. Suzuki T
    5. Tomaru K
    6. Takeno M
    7. Okuda K
    8. Ishigatsubo Y

    (2007) RanBPM, Muskelin, p48EMLP, p44CTLH, and the armadillo-repeat proteins ARMC8alpha and ARMC8beta are components of the CTLH complex

    Gene 396:236–247.

    https://doi.org/10.1016/j.gene.2007.02.032

    • PubMed
    • Google Scholar
32. 1. Komander D
    2. Rape M

    (2012) The ubiquitin code

    Annual Review of Biochemistry 81:203–229.

    https://doi.org/10.1146/annurev-biochem-060310-170328

    • PubMed
    • Google Scholar
33. 1. Lampert F
    2. Stafa D
    3. Goga A
    4. Soste MV
    5. Gilberto S
    6. Olieric N
    7. Picotti P
    8. Stoffel M
    9. Peter M

    (2018) The multi-subunit GID/CTLH E3 ubiquitin ligase promotes cell proliferation and targets the transcription factor Hbp1 for degradation

    eLife 7:e35528.

    https://doi.org/10.7554/eLife.35528

    • PubMed
    • Google Scholar
34. 1. Leal-Esteban LC
    2. Rothé B
    3. Fortier S
    4. Isenschmid M
    5. Constam DB

    (2018) Role of Bicaudal C1 in renal gluconeogenesis and its novel interaction with the CTLH complex

    PLOS Genetics 14:e1007487.

    https://doi.org/10.1371/journal.pgen.1007487

    • PubMed
    • Google Scholar
35. 1. Liu H
    2. Ding J
    3. Köhnlein K
    4. Urban N
    5. Ori A
    6. Villavicencio-Lorini P
    7. Walentek P
    8. Klotz LO
    9. Hollemann T
    10. Pfirrmann T

    (2020) The GID ubiquitin ligase complex is a regulator of AMPK activity and organismal lifespan

    Autophagy 16:1618–1634.

    https://doi.org/10.1080/15548627.2019.1695399

    • PubMed
    • Google Scholar
36. 1. Lu Y
    2. Xie S
    3. Zhang W
    4. Zhang C
    5. Gao C
    6. Sun Q
    7. Cai Y
    8. Xu Z
    9. Xiao M
    10. Xu Y
    11. Huang X
    12. Wu X
    13. Liu W
    14. Wang F
    15. Kang Y
    16. Zhou T

    (2017) Twa1/Gid8 is a β-catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis

    Cell Research 27:1422–1440.

    https://doi.org/10.1038/cr.2017.107

    • PubMed
    • Google Scholar
37. 1. Ma H
    2. Duan J
    3. Ke J
    4. He Y
    5. Gu X
    6. Xu TH
    7. Yu H
    8. Wang Y
    9. Brunzelle JS
    10. Jiang Y
    11. Rothbart SB
    12. Xu HE
    13. Li J
    14. Melcher K

    (2017) A D53 repression motif induces oligomerization of TOPLESS corepressors and promotes assembly of a corepressor-nucleosome complex

    Science Advances 3:e1601217.

    https://doi.org/10.1126/sciadv.1601217

    • PubMed
    • Google Scholar
38. 1. Maitland MER
    2. Onea G
    3. Owens DDG
    4. Gonga-Cavé BC
    5. Wang X
    6. Arrowsmith CH
    7. Barsyte-Lovejoy D
    8. Lajoie GA
    9. Schild-Poulter C

    (2024) Interplay between β-propeller subunits WDR26 and muskelin regulates the CTLH E3 ligase supramolecular complex

    Communications Biology 7:1668.

    https://doi.org/10.1038/s42003-024-07371-3

    • PubMed
    • Google Scholar
39. 1. Martin-Arevalillo R
    2. Nanao MH
    3. Larrieu A
    4. Vinos-Poyo T
    5. Mast D
    6. Galvan-Ampudia C
    7. Brunoud G
    8. Vernoux T
    9. Dumas R
    10. Parcy F

    (2017) Structure of the Arabidopsis TOPLESS corepressor provides insight into the evolution of transcriptional repression

    PNAS 114:8107–8112.

    https://doi.org/10.1073/pnas.1703054114

    • Google Scholar
40. 1. Menon RP
    2. Gibson TJ
    3. Pastore A

    (2004) The C terminus of fragile X mental retardation protein interacts with the multi-domain Ran-binding protein in the microtubule-organising centre

    Journal of Molecular Biology 343:43–53.

    https://doi.org/10.1016/j.jmb.2004.08.024

    • PubMed
    • Google Scholar
41. 1. Mohamed WI
    2. Park SL
    3. Rabl J
    4. Leitner A
    5. Boehringer D
    6. Peter M

    (2021) The human GID complex engages two independent modules for substrate recruitment

    EMBO Reports 22:e52981.

    https://doi.org/10.15252/embr.202152981

    • PubMed
    • Google Scholar
42. 1. Orlacchio A
    2. Kajimura Y
    3. Rizzotto L
    4. Tessari A
    5. Soliman SHA
    6. Visone R
    7. Zhang L
    8. Fries B
    9. Tessarollo L
    10. Amann J
    11. Carbone DP
    12. Lodi A
    13. Ahmed A
    14. Gorgoglione R
    15. Fiermonte G
    16. Freitas M
    17. Palmieri D
    18. Kaufman J
    19. Coppola V

    (2025) RANBP9 and RANBP10 cooperate in regulating non-small cell lung cancer proliferation

    Journal of Experimental & Clinical Cancer Research 44:259.

    https://doi.org/10.1186/s13046-025-03491-8

    • Google Scholar
43. 1. Owens DDG
    2. Maitland MER
    3. Khalili Yazdi A
    4. Song X
    5. Reber V
    6. Schwalm MP
    7. Machado RAC
    8. Bauer N
    9. Wang X
    10. Szewczyk MM
    11. Dong C
    12. Dong A
    13. Loppnau P
    14. Calabrese MF
    15. Dowling MS
    16. Lee J
    17. Montgomery JI
    18. O’Connell TN
    19. Subramanyam C
    20. Wang F
    21. Adamson EC
    22. Schapira M
    23. Gstaiger M
    24. Knapp S
    25. Vedadi M
    26. Min J
    27. Lajoie GA
    28. Barsyte-Lovejoy D
    29. Owen DR
    30. Schild-Poulter C
    31. Arrowsmith CH

    (2024) A chemical probe to modulate human GID4 Pro/N-degron interactions

    Nature Chemical Biology 20:1164–1175.

    https://doi.org/10.1038/s41589-024-01618-0

    • PubMed
    • Google Scholar
44. 1. Palavicini JP
    2. Lloyd BN
    3. Hayes CD
    4. Bianchi E
    5. Kang DE
    6. Dawson-Scully K
    7. Lakshmana MK

    (2013) RanBP9 plays a critical role in neonatal brain development in mice

    PLOS ONE 8:e66908.

    https://doi.org/10.1371/journal.pone.0066908

    • PubMed
    • Google Scholar
45. 1. Palmieri D
    2. Tessari A
    3. Coppola V

    (2018) Scorpins in the DNA damage response

    International Journal of Molecular Sciences 19:1794.

    https://doi.org/10.3390/ijms19061794

    • PubMed
    • Google Scholar
46. 1. Pfirrmann T
    2. Villavicencio-Lorini P
    3. Subudhi AK
    4. Menssen R
    5. Wolf DH
    6. Hollemann T

    (2015) RMND5 from Xenopus laevis is an E3 ubiquitin-ligase and functions in early embryonic forebrain development

    PLOS ONE 10:e0120342.

    https://doi.org/10.1371/journal.pone.0120342

    • PubMed
    • Google Scholar
47. 1. Pham BQ
    2. Yi SA
    3. Ordureau A
    4. An H

    (2025) mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase

    Cell Reports 44:115179.

    https://doi.org/10.1016/j.celrep.2024.115179

    • PubMed
    • Google Scholar
48. 1. Potterton E
    2. Briggs P
    3. Turkenburg M
    4. Dodson E

    (2003) A graphical user interface to the CCP4 program suite

    Acta Crystallographica. Section D, Biological Crystallography 59:1131–1137.

    https://doi.org/10.1107/s0907444903008126

    • PubMed
    • Google Scholar
49. 1. Qiao S
    2. Langlois CR
    3. Chrustowicz J
    4. Sherpa D
    5. Karayel O
    6. Hansen FM
    7. Beier V
    8. von Gronau S
    9. Bollschweiler D
    10. Schäfer T
    11. Alpi AF
    12. Mann M
    13. Prabu JR
    14. Schulman BA

    (2020) Interconversion between anticipatory and active gid e3 ubiquitin ligase conformations via metabolically driven substrate receptor assembly

    Molecular Cell 77:150–163.

    https://doi.org/10.1016/j.molcel.2019.10.009

    • PubMed
    • Google Scholar
50. 1. Regelmann J
    2. Schüle T
    3. Josupeit FS
    4. Horak J
    5. Rose M
    6. Entian KD
    7. Thumm M
    8. Wolf DH

    (2003) Catabolite degradation of fructose-1,6-bisphosphatase in the yeast Saccharomyces cerevisiae: a genome-wide screen identifies eight novel GID genes and indicates the existence of two degradation pathways

    Molecular Biology of the Cell 14:1652–1663.

    https://doi.org/10.1091/mbc.e02-08-0456

    • PubMed
    • Google Scholar
51. 1. Ren J
    2. Li D
    3. Liu J
    4. Liu H
    5. Yan X
    6. Zhu X
    7. Feng W

    (2022) Intertwined Wdr47-NTD dimer recognizes a basic-helical motif in Camsap proteins for proper central-pair microtubule formation

    Cell Reports 41:111589.

    https://doi.org/10.1016/j.celrep.2022.111589

    • PubMed
    • Google Scholar
52. 1. Sherpa D
    2. Chrustowicz J
    3. Qiao S
    4. Langlois CR
    5. Hehl LA
    6. Gottemukkala KV
    7. Hansen FM
    8. Karayel O
    9. von Gronau S
    10. Prabu JR
    11. Mann M
    12. Alpi AF
    13. Schulman BA

    (2021) GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme

    Molecular Cell 81:2445–2459.

    https://doi.org/10.1016/j.molcel.2021.03.025

    • PubMed
    • Google Scholar
53. 1. Sherpa D
    2. Mueller J
    3. Karayel Ö
    4. Xu P
    5. Yao Y
    6. Chrustowicz J
    7. Gottemukkala KV
    8. Baumann C
    9. Gross A
    10. Czarnecki O
    11. Zhang W
    12. Gu J
    13. Nilvebrant J
    14. Sidhu SS
    15. Murray PJ
    16. Mann M
    17. Weiss MJ
    18. Schulman BA
    19. Alpi AF

    (2022) Modular UBE2H-CTLH E2-E3 complexes regulate erythroid maturation

    eLife 11:e77937.

    https://doi.org/10.7554/eLife.77937

    • Google Scholar
54. 1. Simwela NV
    2. Johnston L
    3. Bitar PP
    4. Jaecklein E
    5. Altier C
    6. Sassetti CM
    7. Russell DG

    (2024) Genome-wide screen of Mycobacterium tuberculosis-infected macrophages revealed GID/CTLH complex-mediated modulation of bacterial growth

    Nature Communications 15:9322.

    https://doi.org/10.1038/s41467-024-53637-z

    • PubMed
    • Google Scholar
55. 1. Skraban CM
    2. Wells CF
    3. Markose P
    4. Cho MT
    5. Nesbitt AI
    6. Au PYB
    7. Begtrup A
    8. Bernat JA
    9. Bird LM
    10. Cao K
    11. de Brouwer APM
    12. Denenberg EH
    13. Douglas G
    14. Gibson KM
    15. Grand K
    16. Goldenberg A
    17. Innes AM
    18. Juusola J
    19. Kempers M
    20. Kinning E
    21. Markie DM
    22. Owens MM
    23. Payne K
    24. Person R
    25. Pfundt R
    26. Stocco A
    27. Turner CLS
    28. Verbeek NE
    29. Walsh LE
    30. Warner TC
    31. Wheeler PG
    32. Wieczorek D
    33. Wilkens AB
    34. Zonneveld-Huijssoon E
    35. Kleefstra T
    36. Robertson SP
    37. Santani A
    38. van Gassen KLI
    39. Deardorff MA
    40. Deciphering Developmental Disorders Study

    (2017) WDR26 haploinsufficiency causes a recognizable syndrome of intellectual disability, seizures, abnormal gait, and distinctive facial features

    American Journal of Human Genetics 101:139–148.

    https://doi.org/10.1016/j.ajhg.2017.06.002

    • PubMed
    • Google Scholar
56. 1. Soni S
    2. Bala S
    3. Hanspal M

    (2008) Requirement for erythroblast-macrophage protein (Emp) in definitive erythropoiesis

    Blood Cells, Molecules & Diseases 41:141–147.

    https://doi.org/10.1016/j.bcmd.2008.03.008

    • PubMed
    • Google Scholar
57. 1. Sun F
    2. Cheng Y
    3. Riordan JD
    4. Dupuy A
    5. Dubois W
    6. Pisano M
    7. Dong J
    8. Mock B
    9. Zhan F
    10. Hari P
    11. Janz S

    (2021) WDR26 and MTF2 are therapeutic targets in multiple myeloma

    Journal of Hematology & Oncology 14:203.

    https://doi.org/10.1186/s13045-021-01217-9

    • Google Scholar
58. Website

    1. Tickle IJ
    2. Flensburg C
    3. Keller P
    4. Paciorek W
    5. Sharff A
    6. Vonrhein C
    7. Bricogne G

    (2016) The STARANISO Server

    Accessed April 3, 2026.

    https://staraniso.globalphasing.org/cgi-bin/staraniso.cgi
59. 1. Tomaštíková E
    2. Cenklová V
    3. Kohoutová L
    4. Petrovská B
    5. Váchová L
    6. Halada P
    7. Kočárová G
    8. Binarová P

    (2012) Interactions of an Arabidopsis RanBPM homologue with LisH-CTLH domain proteins revealed high conservation of CTLH complexes in eukaryotes

    BMC Plant Biology 12:83.

    https://doi.org/10.1186/1471-2229-12-83

    • PubMed
    • Google Scholar
60. 1. van gen Hassend PM
    2. Pottikkadavath A
    3. Delto C
    4. Kuhn M
    5. Endres M
    6. Schönemann L
    7. Schindelin H

    (2023) RanBP9 controls the oligomeric state of CTLH complex assemblies

    The Journal of Biological Chemistry 299:102869.

    https://doi.org/10.1016/j.jbc.2023.102869

    • PubMed
    • Google Scholar
61. 1. Varadi M
    2. Anyango S
    3. Deshpande M
    4. Nair S
    5. Natassia C
    6. Yordanova G
    7. Yuan D
    8. Stroe O
    9. Wood G
    10. Laydon A
    11. Žídek A
    12. Green T
    13. Tunyasuvunakool K
    14. Petersen S
    15. Jumper J
    16. Clancy E
    17. Green R
    18. Vora A
    19. Lutfi M
    20. Figurnov M
    21. Cowie A
    22. Hobbs N
    23. Kohli P
    24. Kleywegt G
    25. Birney E
    26. Hassabis D
    27. Velankar S

    (2022) AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models

    Nucleic Acids Research 50:D439–D444.

    https://doi.org/10.1093/nar/gkab1061

    • PubMed
    • Google Scholar
62. 1. Varadi M
    2. Bertoni D
    3. Magana P
    4. Paramval U
    5. Pidruchna I
    6. Radhakrishnan M
    7. Tsenkov M
    8. Nair S
    9. Mirdita M
    10. Yeo J
    11. Kovalevskiy O
    12. Tunyasuvunakool K
    13. Laydon A
    14. Žídek A
    15. Tomlinson H
    16. Hariharan D
    17. Abrahamson J
    18. Green T
    19. Jumper J
    20. Birney E
    21. Steinegger M
    22. Hassabis D
    23. Velankar S

    (2024) AlphaFold Protein Structure Database in 2024: providing structure coverage for over 214 million protein sequences

    Nucleic Acids Research 52:D368–D375.

    https://doi.org/10.1093/nar/gkad1011

    • PubMed
    • Google Scholar
63. 1. Yi SA
    2. Sepic S
    3. Schulman BA
    4. Ordureau A
    5. An H

    (2024) mTORC1-CTLH E3 ligase regulates the degradation of HMG-CoA synthase 1 through the Pro/N-degron pathway

    Molecular Cell 84:2166–2184.

    https://doi.org/10.1016/j.molcel.2024.04.026

    • PubMed
    • Google Scholar
64. 1. Zavortink M
    2. Rutt LN
    3. Dzitoyeva S
    4. Henriksen JC
    5. Barrington C
    6. Bilodeau DY
    7. Wang M
    8. Chen XXL
    9. Rissland OS

    (2020) The E2 Marie Kondo and the CTLH E3 ligase clear deposited RNA binding proteins during the maternal-to-zygotic transition

    eLife 9:e53889.

    https://doi.org/10.7554/eLife.53889

    • PubMed
    • Google Scholar
65. 1. Zeinali E
    2. Mashayekhi F
    3. Farraj RA
    4. Hasanni T
    5. Caron MC
    6. Coulombe Y
    7. Fitieh A
    8. Glover JNM
    9. Masson JY
    10. Ismail IH

    (2025) Pathogenic variants in MAEA disrupt DNA replication fork stability and are associated with developmental abnormalities in humans

    Science Advances 11:eadv0381.

    https://doi.org/10.1126/sciadv.adv0381

    • PubMed
    • Google Scholar
66. 1. Zhen R
    2. Moo C
    3. Zhao Z
    4. Chen M
    5. Feng H
    6. Zheng X
    7. Zhang L
    8. Shi J
    9. Chen C

    (2020) Wdr26 regulates nuclear condensation in developing erythroblasts

    Blood 135:208–219.

    https://doi.org/10.1182/blood.2019002165

    • PubMed
    • Google Scholar
67. 1. Zheng N
    2. Shabek N

    (2017) Ubiquitin ligases: structure, function, and regulation

    Annual Review of Biochemistry 86:129–157.

    https://doi.org/10.1146/annurev-biochem-060815-014922

    • PubMed
    • Google Scholar

Author details

1. Pia Maria van gen Hassend

   Institute of Structural Biology, Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universität Würzburg, Würzburg, Germany

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1245-4339

2. Hermann Schindelin

   Institute of Structural Biology, Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universität Würzburg, Würzburg, Germany

   Contribution

   Conceptualization, Supervision, Funding acquisition, Investigation, Writing – review and editing

   For correspondence

   hermann.schindelin@virchow.uni-wuerzburg.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2067-3187

• 241

  views

• 17

  downloads

• 0

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.