The spatial architecture of protein function and adaptation

Richard N. McLaughlin, Frank J. Poelwijk, Arjun Raman, Walraj S. Gosal, Rama Ranganathan

Research output: Contribution to journalArticle

207 Citations (Scopus)

Abstract

Statistical analysis of protein evolution suggests a design for natural proteins in which sparse networks of coevolving amino acids (termed sectors) comprise the essence of three-dimensional structure and function. However, proteins are also subject to pressures deriving from the dynamics of the evolutionary process itself-the ability to tolerate mutation and to be adaptive to changing selection pressures. To understand the relationship of the sector architecture to these properties, we developed a high-throughput quantitative method for a comprehensive single-mutation study in which every position is substituted individually to every other amino acid. Using a PDZ domain (PSD95 pdz3) model system, we show that sector positions are functionally sensitive to mutation, whereas non-sector positions are more tolerant to substitution. In addition, we find that adaptation to a new binding specificity initiates exclusively through variation within sector residues. A combination of just two sector mutations located near and away from the ligand-binding site suffices to switch the binding specificity of PSD95 pdz3 quantitatively towards a class-switching ligand. The localization of functional constraint and adaptive variation within the sector has important implications for understanding and engineering proteins.

Original languageEnglish (US)
Pages (from-to)138-142
Number of pages5
JournalNature
Volume491
Issue number7422
DOIs
StatePublished - Nov 1 2012

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Mutation
Proteins
Immunoglobulin Class Switching
PDZ Domains
Ligands
Protein Engineering
Amino Acids
Pressure
Binding Sites

ASJC Scopus subject areas

  • General

Cite this

McLaughlin, R. N., Poelwijk, F. J., Raman, A., Gosal, W. S., & Ranganathan, R. (2012). The spatial architecture of protein function and adaptation. Nature, 491(7422), 138-142. https://doi.org/10.1038/nature11500

The spatial architecture of protein function and adaptation. / McLaughlin, Richard N.; Poelwijk, Frank J.; Raman, Arjun; Gosal, Walraj S.; Ranganathan, Rama.

In: Nature, Vol. 491, No. 7422, 01.11.2012, p. 138-142.

Research output: Contribution to journalArticle

McLaughlin, RN, Poelwijk, FJ, Raman, A, Gosal, WS & Ranganathan, R 2012, 'The spatial architecture of protein function and adaptation', Nature, vol. 491, no. 7422, pp. 138-142. https://doi.org/10.1038/nature11500
McLaughlin RN, Poelwijk FJ, Raman A, Gosal WS, Ranganathan R. The spatial architecture of protein function and adaptation. Nature. 2012 Nov 1;491(7422):138-142. https://doi.org/10.1038/nature11500
McLaughlin, Richard N. ; Poelwijk, Frank J. ; Raman, Arjun ; Gosal, Walraj S. ; Ranganathan, Rama. / The spatial architecture of protein function and adaptation. In: Nature. 2012 ; Vol. 491, No. 7422. pp. 138-142.
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