A structural dissection of amino acid substitutions in helical transmembrane proteins

Younes Mokrab, Tim J. Stevens, Kenji Mizuguchi

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The evolution of protein folds is under strong constraints from their surrounding environment. Although folding in water-soluble proteins is driven primarily by hydrophobic forces, the nature of the forces that determine the folding and stability of transmembrane proteins are still not fully understood. Furthermore, the chemically heterogeneous lipid bilayer has a non-uniform effect on protein structure. In this article, we attempt to get an insight into the nature of this effect by examining the impact of various types of local structure environment on amino acid substitution, based on alignments of high-resolution structures of polytopic helical transmembrane proteins combined with sequences of close homologs. Compared to globular proteins, burying amino acid sidechains, especially hydrophilic ones, led to a lower increase in conservation in both the lipid-water interface region and the hydrocarbon core region. This observation is due to surface residues in HTM proteins especially in the HC region being relatively highly conserved, suggesting higher evolutionary constraints from their specific interactions with the surrounding lipid molecules. Polar and small residues, particularly Pro and Gly, show a noticeable increase in conservation as they are positioned more towards the centre of the membrane, which is consistent with their recognized key roles in structural stability. In addition, the examination of hydrogen bonds in the membrane environment identified some exposed hydrophilic residues being better conserved when not hydrogen-bonded to other residues, supporting the importance of lipid-protein sidechain interactions. The conclusions presented in this study highlight the distinct features of substitution matrices that take into account the membrane environment, and their potential role in improving sequence-structure alignments of transmembrane proteins.

Original languageEnglish
Pages (from-to)2895-2907
Number of pages13
JournalProteins: Structure, Function and Bioinformatics
Volume78
Issue number14
DOIs
Publication statusPublished - 1 Nov 2010
Externally publishedYes

Fingerprint

Dissection
Amino Acid Substitution
Substitution reactions
Amino Acids
Proteins
Lipids
Membranes
Hydrogen
Conservation
Water
Protein Stability
Sequence Alignment
Lipid Bilayers
Lipid bilayers
Sequence Homology
Hydrocarbons
Hydrogen bonds
Molecules

Keywords

  • Amino acid substitution
  • Helical transmembrane proteins
  • Lipid bilayer
  • Local structure environment
  • Protein structure
  • Structural bioinformatics

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Cite this

A structural dissection of amino acid substitutions in helical transmembrane proteins. / Mokrab, Younes; Stevens, Tim J.; Mizuguchi, Kenji.

In: Proteins: Structure, Function and Bioinformatics, Vol. 78, No. 14, 01.11.2010, p. 2895-2907.

Research output: Contribution to journalArticle

@article{c4d8ae1f81e942489207bd01e1382727,
title = "A structural dissection of amino acid substitutions in helical transmembrane proteins",
abstract = "The evolution of protein folds is under strong constraints from their surrounding environment. Although folding in water-soluble proteins is driven primarily by hydrophobic forces, the nature of the forces that determine the folding and stability of transmembrane proteins are still not fully understood. Furthermore, the chemically heterogeneous lipid bilayer has a non-uniform effect on protein structure. In this article, we attempt to get an insight into the nature of this effect by examining the impact of various types of local structure environment on amino acid substitution, based on alignments of high-resolution structures of polytopic helical transmembrane proteins combined with sequences of close homologs. Compared to globular proteins, burying amino acid sidechains, especially hydrophilic ones, led to a lower increase in conservation in both the lipid-water interface region and the hydrocarbon core region. This observation is due to surface residues in HTM proteins especially in the HC region being relatively highly conserved, suggesting higher evolutionary constraints from their specific interactions with the surrounding lipid molecules. Polar and small residues, particularly Pro and Gly, show a noticeable increase in conservation as they are positioned more towards the centre of the membrane, which is consistent with their recognized key roles in structural stability. In addition, the examination of hydrogen bonds in the membrane environment identified some exposed hydrophilic residues being better conserved when not hydrogen-bonded to other residues, supporting the importance of lipid-protein sidechain interactions. The conclusions presented in this study highlight the distinct features of substitution matrices that take into account the membrane environment, and their potential role in improving sequence-structure alignments of transmembrane proteins.",
keywords = "Amino acid substitution, Helical transmembrane proteins, Lipid bilayer, Local structure environment, Protein structure, Structural bioinformatics",
author = "Younes Mokrab and Stevens, {Tim J.} and Kenji Mizuguchi",
year = "2010",
month = "11",
day = "1",
doi = "10.1002/prot.22809",
language = "English",
volume = "78",
pages = "2895--2907",
journal = "Proteins: Structure, Function and Bioinformatics",
issn = "0887-3585",
publisher = "Wiley-Liss Inc.",
number = "14",

}

TY - JOUR

T1 - A structural dissection of amino acid substitutions in helical transmembrane proteins

AU - Mokrab, Younes

AU - Stevens, Tim J.

AU - Mizuguchi, Kenji

PY - 2010/11/1

Y1 - 2010/11/1

N2 - The evolution of protein folds is under strong constraints from their surrounding environment. Although folding in water-soluble proteins is driven primarily by hydrophobic forces, the nature of the forces that determine the folding and stability of transmembrane proteins are still not fully understood. Furthermore, the chemically heterogeneous lipid bilayer has a non-uniform effect on protein structure. In this article, we attempt to get an insight into the nature of this effect by examining the impact of various types of local structure environment on amino acid substitution, based on alignments of high-resolution structures of polytopic helical transmembrane proteins combined with sequences of close homologs. Compared to globular proteins, burying amino acid sidechains, especially hydrophilic ones, led to a lower increase in conservation in both the lipid-water interface region and the hydrocarbon core region. This observation is due to surface residues in HTM proteins especially in the HC region being relatively highly conserved, suggesting higher evolutionary constraints from their specific interactions with the surrounding lipid molecules. Polar and small residues, particularly Pro and Gly, show a noticeable increase in conservation as they are positioned more towards the centre of the membrane, which is consistent with their recognized key roles in structural stability. In addition, the examination of hydrogen bonds in the membrane environment identified some exposed hydrophilic residues being better conserved when not hydrogen-bonded to other residues, supporting the importance of lipid-protein sidechain interactions. The conclusions presented in this study highlight the distinct features of substitution matrices that take into account the membrane environment, and their potential role in improving sequence-structure alignments of transmembrane proteins.

AB - The evolution of protein folds is under strong constraints from their surrounding environment. Although folding in water-soluble proteins is driven primarily by hydrophobic forces, the nature of the forces that determine the folding and stability of transmembrane proteins are still not fully understood. Furthermore, the chemically heterogeneous lipid bilayer has a non-uniform effect on protein structure. In this article, we attempt to get an insight into the nature of this effect by examining the impact of various types of local structure environment on amino acid substitution, based on alignments of high-resolution structures of polytopic helical transmembrane proteins combined with sequences of close homologs. Compared to globular proteins, burying amino acid sidechains, especially hydrophilic ones, led to a lower increase in conservation in both the lipid-water interface region and the hydrocarbon core region. This observation is due to surface residues in HTM proteins especially in the HC region being relatively highly conserved, suggesting higher evolutionary constraints from their specific interactions with the surrounding lipid molecules. Polar and small residues, particularly Pro and Gly, show a noticeable increase in conservation as they are positioned more towards the centre of the membrane, which is consistent with their recognized key roles in structural stability. In addition, the examination of hydrogen bonds in the membrane environment identified some exposed hydrophilic residues being better conserved when not hydrogen-bonded to other residues, supporting the importance of lipid-protein sidechain interactions. The conclusions presented in this study highlight the distinct features of substitution matrices that take into account the membrane environment, and their potential role in improving sequence-structure alignments of transmembrane proteins.

KW - Amino acid substitution

KW - Helical transmembrane proteins

KW - Lipid bilayer

KW - Local structure environment

KW - Protein structure

KW - Structural bioinformatics

UR - http://www.scopus.com/inward/record.url?scp=77958003820&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77958003820&partnerID=8YFLogxK

U2 - 10.1002/prot.22809

DO - 10.1002/prot.22809

M3 - Article

VL - 78

SP - 2895

EP - 2907

JO - Proteins: Structure, Function and Bioinformatics

JF - Proteins: Structure, Function and Bioinformatics

SN - 0887-3585

IS - 14

ER -