Structure of the GOLD-domain seven-transmembrane helix protein family member TMEM87A

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Abstract

TMEM87s are eukaryotic transmembrane proteins with two members (TMEM87A and TMEM87B) in humans. TMEM87s have proposed roles in protein transport to and from the Golgi, as mechanosensitive ion channels, and in developmental signaling. TMEM87 disruption has been implicated in cancers and developmental disorders. To better understand TMEM87 structure and function, we determined a cryo-EM structure of human TMEM87A in lipid nanodiscs. TMEM87A consists of a Golgi-dynamics (GOLD) domain atop a membrane spanning seven-transmembrane helix domain with a large cavity open to solution and the membrane outer leaflet. Structural and functional analyses suggest TMEM87A may not function as an ion channel or G-protein coupled receptor. We find TMEM87A shares its characteristic domain arrangement with seven other proteins in humans; three that had been identified as evolutionary related (TMEM87B, GPR107, and GPR108) and four previously unrecognized homologs (GPR180, TMEM145, TMEM181, and WLS)). Among these structurally related GOLD domain seven-transmembrane helix (GOST) proteins, WLS is best characterized as a membrane trafficking and secretion chaperone for lipidated Wnt signaling proteins. We find key structural determinants for WLS function are conserved in TMEM87A. We propose TMEM87A and structurally homologous GOST proteins could serve a common role in trafficking membrane-associated cargo.

Data availability

All data associated with this study ware publicly available. The TMEM87A model is in the Protein Data Bank (PDB) under 8CTJ, the final maps are in the Electron Microscopy Data Bank (EMDB) under EMD-26992, and the original micrograph movies and final particle stack are in the Electron Microscopy Public Image Archive (EMPIAR) under EMPIAR-11045.

The following data sets were generated

(2022) Cryo-EM structure of TMEM87A
Protein Data Bank, doi: 10.2210/pdb8CTJ/pdb.

https://www.rcsb.org/structure/8CTJ
(2022) Cryo-EM structure of TMEM87A
Electron Microscopy Data Bank (EMDB) under EMD-26992.

https://www.ebi.ac.uk/emdb/EMD-26992
(2022) Cryo-EM structure of the GOLD-domain seven-transmembrane protein TMEM87A
Electron Microscopy Public Image Archive (EMPIAR) under EMPIAR-11045.

https://www.ebi.ac.uk/empiar/EMPIAR-11045/

Article and author information

Author details

Christopher M Hoel

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Lin Zhang

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Stephen G Brohawn

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

For correspondence
brohawn@berkeley.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6768-3406

Funding

New York Stem Cell Foundation

Stephen G Brohawn

National Institute of General Medical Sciences (GM123496)

Stephen G Brohawn

McKnight Foundation

Stephen G Brohawn

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.