Document Detail


The spatial architecture of protein function and adaptation.
MedLine Citation:
PMID:  23041932     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Richard N McLaughlin; Frank J Poelwijk; Arjun Raman; Walraj S Gosal; Rama Ranganathan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-07
Journal Detail:
Title:  Nature     Volume:  491     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-06     Completed Date:  2012-12-26     Revised Date:  2014-04-22    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  138-42     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adaptation, Physiological* / genetics,  physiology
Amino Acid Sequence
Amino Acid Substitution*
Binding Sites / genetics
Evolution, Molecular
Ligands
Models, Molecular
Molecular Sequence Data
Mutant Proteins / chemistry*,  genetics,  metabolism
Mutation
PDZ Domains / genetics*,  physiology*
Proteins / chemistry*,  genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
R01 EY018720/EY/NEI NIH HHS; R01EY018720-05/EY/NEI NIH HHS
Chemical
Reg. No./Substance:
0/Ligands; 0/Mutant Proteins; 0/Proteins
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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