1. Structural Biology and Molecular Biophysics
Download icon

Sequence co-evolution gives 3D contacts and structures of protein complexes

  1. Thomas A Hopf
  2. Charlotta P.I Schärfe
  3. João P.G.L.M Rodrigues
  4. Anna G Green
  5. Oliver Kohlbacher
  6. Chris Sander
  7. Alexandre M.J.J. Bonvin
  8. Debora S Marks  Is a corresponding author
  1. Harvard University, United States
  2. University of Tübingen, Germany
  3. Bijvoet Center for Biomolecular Research, Utrecht University, Netherlands
  4. Harvard Medical School, United States
  5. Memorial Sloan Kettering Cancer Center, United States
Research Article
  • Cited 221
  • Views 13,723
  • Annotations
Cite this article as: eLife 2014;3:e03430 doi: 10.7554/eLife.03430

Abstract

Protein-protein interactions are fundamental to many biological processes. Experimental screens have identified tens of thousands of interactions and structural biology has provided detailed functional insight for select 3D protein complexes. An alternative rich source of information about protein interactions is the evolutionary sequence record. Building on earlier work, we show that analysis of correlated evolutionary sequence changes across proteins identifies residues that are close in space with sufficient accuracy to determine the three-dimensional structure of the protein complexes. We evaluate prediction performance in blinded tests on 76 complexes of known 3D structure, predict protein-protein contacts in 32 complexes of unknown structure, and demonstrate how evolutionary couplings can be used to distinguish between interacting and non-interacting protein pairs in a large complex. With the current growth of sequences, we expect that the method can be generalized to genome-wide elucidation of protein-protein interaction networks and used for interaction predictions at residue resolution.

Article and author information

Author details

  1. Thomas A Hopf

    Harvard University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Charlotta P.I Schärfe

    University of Tübingen, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. João P.G.L.M Rodrigues

    Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Anna G Green

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Oliver Kohlbacher

    University of Tübingen, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Chris Sander

    Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Alexandre M.J.J. Bonvin

    Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Debora S Marks

    Harvard University, Boston, United States
    For correspondence
    debbie@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. John Kuriyan, Howard Hughes Medical Institute, University of California, Berkeley, United States

Publication history

  1. Received: May 21, 2014
  2. Accepted: September 23, 2014
  3. Accepted Manuscript published: September 25, 2014 (version 1)
  4. Version of Record published: November 3, 2014 (version 2)

Copyright

© 2014, Hopf 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

  • 13,723
    Page views
  • 2,081
    Downloads
  • 221
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

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)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Structural Biology and Molecular Biophysics
    Danish Khan et al.
    Research Article

    Yeast Sfh5 is an unusual member of the Sec14-like phosphatidylinositol transfer protein (PITP) family. Whereas PITPs are defined by their abilities to transfer phosphatidylinositol between membranes in vitro, and to stimulate phosphoinositide signaling in vivo, Sfh5 does not exhibit these activities. Rather, Sfh5 is a redox-active penta-coordinate high spin FeIII hemoprotein with an unusual heme-binding arrangement that involves a co-axial tyrosine/histidine coordination strategy and a complex electronic structure connecting the open shell iron d-orbitals with three aromatic ring systems. That Sfh5 is not a PITP is supported by demonstrations that heme is not a readily exchangeable ligand, and that phosphatidylinositol-exchange activity is resuscitated in heme binding-deficient Sfh5 mutants. The collective data identify Sfh5 as the prototype of a new class of fungal hemoproteins, and emphasize the versatility of the Sec14-fold as scaffold for translating the binding of chemically distinct ligands to the control of diverse sets of cellular activities.

    1. Structural Biology and Molecular Biophysics
    Faxiang Li et al.
    Research Article

    The dynamic tyrosination-detyrosination cycle of α-tubulin regulates microtubule functions. Perturbation of this cycle impairs mitosis, neural physiology, and cardiomyocyte contraction. The carboxypeptidases vasohibins 1 and 2 (VASH1 and VASH2), in complex with the small vasohibin-binding protein (SVBP), mediate α-tubulin detyrosination. These enzymes detyrosinate microtubules more efficiently than soluble αβ-tubulin heterodimers. The structural basis for this substrate preference is not understood. Using cryo-electron microscopy (cryo-EM), we have determined the structure of human VASH1-SVBP bound to microtubules. The acidic C-terminal tail of α-tubulin binds to a positively charged groove near the active site of VASH1. VASH1 forms multiple additional contacts with the globular domain of α-tubulin, including contacts with a second α-tubulin in an adjacent protofilament. Simultaneous engagement of two protofilaments by VASH1 can only occur within the microtubule lattice, but not with free αβ heterodimers. These lattice-specific interactions enable preferential detyrosination of microtubules by VASH1.