Publikationsdatum:
2012-10-09
Beschreibung:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991786/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991786/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McLaughlin, Richard N Jr -- Poelwijk, Frank J -- Raman, Arjun -- Gosal, Walraj S -- Ranganathan, Rama -- R01 EY018720/EY/NEI NIH HHS/ -- R01EY018720-05/EY/NEI NIH HHS/ -- England -- Nature. 2012 Nov 1;491(7422):138-42. doi: 10.1038/nature11500. Epub 2012 Oct 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23041932" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
*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
Print ISSN:
0028-0836
Digitale ISSN:
1476-4687
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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