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Structural and functional constraints in the evolution of protein families

Nature Reviews Molecular Cell Biology volume 10, pages 709–720 (2009)Cite this article

Key Points

  • The process of protein evolution is balanced between Darwinian selection for functionally advantageous mutations and neutral evolution, in which acceptance of amino acid substitution is constrained by the requirement for proper protein structure and function.

  • Comparative analyses of homologous proteins allow conserved features in both sequence and structure to be identified, along with constraints that give rise to distinct patterns of protein evolution.

  • The local structural environment of amino acids in the three-dimensional structures of proteins influences the probability of substitution during protein evolution. Solvent accessibility is the most important determinant, followed by the existence of hydrogen bonds from side-chain to main-chain groups and the nature of the element of secondary structure to which the amino acid contributes.

  • Solvent-inaccessible polar side chains provide strong structural and functional constraints in the evolution of protein families and can give rise to characteristic architectural motifs that are born from the need to satisfy hydrogen bonding.

  • Functional constraints operate through the requirement to maintain the interaction of proteins with other macromolecules in assemblies or with substrates, ligands or allosteric regulators.

  • Functional residues are under greater pressure to be conserved throughout the evolution process, in which they remain crucially important to the activity of proteins and thus to the selective advantage of the organism.

  • Structural and functional constraints in the evolution of protein families can be illustrated by the roles and properties of individual amino acids in the three-dimensional structure of proteins. Although it is an essential prerequisite to understanding protein evolution, further insights will depend on integrated and multidisciplinary systems approaches.

Abstract

 See more Darwin-related content in our Nature Publishing Group collection.

High-throughput genomic sequencing has focused attention on understanding differences between species and between individuals. When this genetic variation affects protein sequences, the rate of amino acid substitution reflects both Darwinian selection for functionally advantageous mutations and selectively neutral evolution operating within the constraints of structure and function. During neutral evolution, whereby mutations accumulate by random drift, amino acid substitutions are constrained by factors such as the formation of intramolecular and intermolecular interactions and the accessibility to water or lipids surrounding the protein. These constraints arise from the need to conserve a specific architecture and to retain interactions that mediate functions in protein families and superfamilies.

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Figure 1: Results of hierarchical clustering of 64 environments.
Figure 2: Structural constraints on pepsin-like aspartic proteinases.
Figure 3: Conserved polar residues that span secondary structures.
Figure 4: Conserved polar residues that support loops.

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Acknowledgements

C.L.W. was funded by a Biotechnology and Biological Sciences Research Council studentship. S.G. was supported by the BiO foundation. T.L.B. is funded by the Wellcome Trust.

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Authors and Affiliations

  1. Biochemistry Department, University of Cambridge, Cambridge, CB2 1GA, UK

    Catherine L. Worth, Sungsam Gong & Tom L. Blundell

  2. Leibniz-Institut für Molekulare Pharmakologie, Campus Berlin-Buch, Berlin, 13125, Germany

    Catherine L. Worth

Authors
  1. Catherine L. Worth
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  2. Sungsam Gong
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  3. Tom L. Blundell
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Corresponding author

Correspondence to Tom L. Blundell.

Supplementary information

Related links

Related links

DATABASES

PDB

 1gk8

1m2z

1tme

2fgf

3app

5pal

FURTHER INFORMATION

The Blundell group's homepage

CATH

CDD

CE

Dali

ESSTs

Gene3D

HOMSTRAD

InterPro

JOY

MMDB

PairsDB

PASS2

Pfam

Phylofacts

Prints

ProDom

PROSITE

PyMol

SCOP

SMART

Superfamily

TIFRFAMs

Toccata

Ulla

Glossary

Chaperone

A protein that assists in the folding or unfolding and the assembly or disassembly of other macromolecular structures.

Neutral drift

The process whereby random sampling effects over successive generations give rise to stochastic changes in the allele frequencies within a population.

β-lactamase

An enzyme produced by some bacteria that confers resistance to β-lactam antibiotics.

Constraint

A structural and dynamic system, or functional factor, that influences the acceptance of amino acid substitutions that occur in divergent protein families. Given that selection occurs at the level of the organism and that individual proteins and the systems in which they evolve are plastic, these constraints tend not to 'force' but rather to 'restrain' the substitutions that occur in evolution.

Orthologues

Genes (or gene products) descended from a common ancestral origin that diverged as a result of a speciation event.

Hydrogen bonding potential

The capacity of atoms to act as proton donors or acceptors in the formation of hydrogen bonds.

Jelly roll

An eight-stranded β-sandwich that is formed by four Greek key motifs, each consisting of four sequential antiparallel β-strands.

β-propeller

An all-β protein architecture comprising four to eight blade-shaped β-sheets arranged toroidally around a central axis.

α-helical bundle

A protein fold consisting of multiple α-helices that are approximately parallel to one another.

αβ-Rossman fold

Two repeating β–α–β super-secondary motifs.

Distance matrix

An n×n array that represents the distances between a set of n elements.

Positive φ main-chain torsion angle

A positive dihedral angle around the nitrogen–α-carbon bonds in the protein main chain. For L-amino acids these bond angles are generally restricted to a negative value owing to steric hindrance from the side chains, but they can be positive when there is no side chain (Gly) or when polar side-chain interactions with the main-chain peptide units stabilize this conformation.

van der Waals interaction

A weak electrostatic interaction that is formed by the fluctuating electron clouds of two atoms.

Tyr corner motif

A motif that involves a conserved Tyr within Greek key proteins forming a hydrogen bond with the local protein backbone in an adjacent loop.

Cation–π interaction

A non-covalent interaction between an aromatic side chain and a cationic side chain.

SH3 domain

(Src homology 3 domain). A small domain that is found in various intracellular or membrane-associated proteins and has a β-barrel fold.

Euclidean distance

A geometric distance between two point sets in the n-dimensional (or Euclidean) space.

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Worth, C., Gong, S. & Blundell, T. Structural and functional constraints in the evolution of protein families. Nat Rev Mol Cell Biol 10, 709–720 (2009). https://doi.org/10.1038/nrm2762

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