Codon-level information improves predictions of inter-residue contacts in proteins by correlated mutation analysis

  1. Etai Jacob
  2. Ron Unger
  3. Amnon Horovitz  Is a corresponding author
  1. Bar-Ilan University, Israel
  2. Weizmann Institute of Science, Israel

Abstract

Methods for analysing correlated mutations in proteins are becoming an increasingly powerful tool for predicting contacts within and between proteins. Nevertheless, limitations remain due to the requirement for large multiple sequence alignments (MSA) and the fact that, in general, only the relatively small number of top-ranking predictions are reliable. To date, methods for analysing correlated mutations have relied exclusively on amino acid MSAs as inputs. Here, we describe a new approach for analysing correlated mutations that is based on combined analysis of amino acid and codon MSAs. We show that a direct contact is more likely to be present when the correlation between the positions is strong at the amino acid level but weak at the codon level. The performance of different methods for analysing correlated mutations in predicting contacts is shown to be enhanced significantly when amino acid and codon data are combined.

Article and author information

Author details

  1. Etai Jacob

    The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Ron Unger

    The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Amnon Horovitz

    Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel
    For correspondence
    Amnon.Horovitz@weizmann.ac.il
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Michael Levitt, Stanford University, United States

Publication history

  1. Received: May 22, 2015
  2. Accepted: September 13, 2015
  3. Accepted Manuscript published: September 15, 2015 (version 1)
  4. Accepted Manuscript updated: September 25, 2015 (version 2)
  5. Version of Record published: October 13, 2015 (version 3)

Copyright

© 2015, Jacob 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

  • 2,960
    Page views
  • 585
    Downloads
  • 6
    Citations

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

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)

  1. Etai Jacob
  2. Ron Unger
  3. Amnon Horovitz
(2015)
Codon-level information improves predictions of inter-residue contacts in proteins by correlated mutation analysis
eLife 4:e08932.
https://doi.org/10.7554/eLife.08932

Further reading

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Atefeh Rafiei et al.
    Research Article Updated

    Doublecortin (DCX) is a microtubule (MT)-associated protein that regulates MT structure and function during neuronal development and mutations in DCX lead to a spectrum of neurological disorders. The structural properties of MT-bound DCX that explain these disorders are incompletely determined. Here, we describe the molecular architecture of the DCX–MT complex through an integrative modeling approach that combines data from X-ray crystallography, cryo-electron microscopy, and a high-fidelity chemical crosslinking method. We demonstrate that DCX interacts with MTs through its N-terminal domain and induces a lattice-dependent self-association involving the C-terminal structured domain and its disordered tail, in a conformation that favors an open, domain-swapped state. The networked state can accommodate multiple different attachment points on the MT lattice, all of which orient the C-terminal tails away from the lattice. As numerous disease mutations cluster in the C-terminus, and regulatory phosphorylations cluster in its tail, our study shows that lattice-driven self-assembly is an important property of DCX.

    1. Structural Biology and Molecular Biophysics
    Siyoung Kim et al.
    Research Article Updated

    Lipid droplets (LDs) are organelles formed in the endoplasmic reticulum (ER) to store triacylglycerol (TG) and sterol esters. The ER protein seipin is key for LD biogenesis. Seipin forms a cage-like structure, with each seipin monomer containing a conserved hydrophobic helix and two transmembrane (TM) segments. How the different parts of seipin function in TG nucleation and LD budding is poorly understood. Here, we utilized molecular dynamics simulations of human seipin, along with cell-based experiments, to study seipin’s functions in protein–lipid interactions, lipid diffusion, and LD maturation. An all-atom simulation indicates that seipin TM segment residues and hydrophobic helices residues located in the phospholipid tail region of the bilayer attract TG. Simulating larger, growing LDs with coarse-grained models, we find that the seipin TM segments form a constricted neck structure to facilitate conversion of a flat oil lens into a budding LD. Using cell experiments and simulations, we also show that conserved, positively charged residues at the end of seipin’s TM segments affect LD maturation. We propose a model in which seipin TM segments critically function in TG nucleation and LD growth.