| The spatial architecture of protein function and adaptation. | |
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MedLine Citation:
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PMID: 23041932 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Richard N McLaughlin Jr; Frank J Poelwijk; Arjun Raman; Walraj S Gosal; Rama Ranganathan |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-07 |
Journal Detail:
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Title: Nature Volume: - ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1] Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, USA [2] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, USA [3] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109-1024, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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