Emergence and evolution of an interaction between intrinsically disordered proteins
- Uppsala University, Sweden
- University of Cambridge, United Kingdom
- ETH Zürich, Switzerland
Abstract
Protein-protein interactions involving intrinsically disordered proteins are important for cellular function and common in all organisms. However, it is not clear how such interactions emerge and evolve on a molecular level. We performed phylogenetic reconstruction, resurrection and biophysical characterization of two interacting disordered protein domains, CID and NCBD. CID appeared after the divergence of protostomes and deuterostomes 450-600 million years ago, while NCBD was present in the protostome/deuterostome ancestor. The most ancient CID/NCBD formed a relatively weak complex (Kd~5 μM). At the time of the first vertebrate-specific whole genome duplication the affinity had increased (Kd~200 nM) and was maintained in further speciation. Experiments together with molecular modeling using NMR chemical shifts suggest that new interactions involving intrinsically disordered proteins may evolve via a low affinity complex which is optimized by modulating direct interactions as well as dynamics, while tolerating several potentially disruptive mutations.
Data availability
-
EnsemblPublicly available at the Ensembl.
-
Japanese lamprey genome projectPublicly available at the Japanese Lamprey Genome Project.
-
OrcAPublicly available at the Bioinformatics and Evolutionary Genomics.
Article and author information
Author details
Michele Vendruscolo
Funding
Vetenskapsrådet
- Per Jemth
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Hultqvist et al.
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.
Metrics
-
- 5,335
- views
-
- 995
- downloads
-
- 43
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Emergence and evolution of an interaction between intrinsically disordered proteins
eLife 6:e16059.
https://doi.org/10.7554/eLife.16059
Further reading
-
- Structural Biology and Molecular Biophysics
Complementary structural biology approaches reveal how an agonist and a covalent inhibitor simultaneously bind to a nuclear receptor.
-
- Structural Biology and Molecular Biophysics
The M2 proton channel aids in the exit of mature influenza viral particles from the host plasma membrane through its ability to stabilize regions of high negative gaussian curvature (NGC) that occur at the neck of budding virions. The channels are homo-tetramers that contain a cytoplasm-facing amphipathic helix (AH) that is necessary and sufficient for NGC generation; however, constructs containing the transmembrane spanning helix, which facilitates tetramerization, exhibit enhanced curvature generation. Here we used all-atom molecular dynamics (MD) simulations to explore the conformational dynamics of M2 channels in lipid bilayers revealing that the AH is dynamic, quickly breaking the 4-fold symmetry observed in most structures. Next, we carried out MD simulations with the protein restrained in 4-fold and 2-fold symmetric conformations to determine the impact on the membrane shape. While each pattern was distinct, all configurations induced pronounced curvature in the outer leaflet, while conversely, the inner leaflets showed minimal curvature and significant lipid tilt around the AHs. The MD-generated profiles at the protein-membrane interface were then extracted and used as boundary conditions in a continuum elastic membrane model to calculate the membrane bending energy of each conformation embedded in different membrane surfaces characteristic of a budding virus. The calculations show that all three M2 conformations are stabilized in inward-budding, concave spherical caps and destabilized in outward-budding, convex spherical caps, the latter reminiscent of a budding virus. One of the C2-broken symmetry conformations is stabilized by 4 kT in NGC surfaces with the minimum energy conformation occurring at a curvature corresponding to 33 nm radii. In total, our work provides atomistic insight into the curvature sensing capabilities of M2 channels and how enrichment in the nascent viral particle depends on protein shape and membrane geometry.
