Evolution-guided engineering of serine protease specificity
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1
UT Southwestern Medical Center, Pharmacology / Green Center for Systems Biology, United States
Proteins are remarkable for their ability to evolve new functional specificity over relatively short mutational paths. This process is poorly understood, and attempts to alter specificity based on structural intuition rely heavily on trial and error and lack an underlying principle. We have recently described a statistical analysis of coevolution in proteins (Statistical Coupling Analysis, or SCA) that suggests a novel approach to specificity engineering. In the family of S1A Serine Proteases, SCA has identified a set of coevolving residues (a "sector") that predicts and controls substrate specificity, but has evolved independently of sectors influencing stability or catalytic activity. Thus, SCA provides a clear prediction of residues that can be used to alter specificity independent of these other properties. Furthermore, the pattern of coevolution between positions suggests a structurally non-intuitive path of mutagenesis that could recapitulate an evolutionarily plausible route for functional divergence in this family. We are testing these hypotheses by designing proteins with mutations in the SCA specificity sector and assaying their functional properties in the laboratory.
References
1. Lockless SW, Ranganathan R (1999) Evolutionarily conserved pathways of energetic connectivity in protein families. Science 286(5438):295-9.
2. Halabi N, et al. (2009) Protein sectors: evolutionary units of three-dimensional structure. Cell 138(4):774-86
Conference:
Neuroinformatics 2010 , Kobe, Japan, 30 Aug - 1 Sep, 2010.
Presentation Type:
Poster Presentation
Topic:
Genomics and genetics
Citation:
Russ
W and
Ranganathan
R
(2010). Evolution-guided engineering of serine protease specificity.
Front. Neurosci.
Conference Abstract:
Neuroinformatics 2010 .
doi: 10.3389/conf.fnins.2010.13.00060
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Received:
11 Jun 2010;
Published Online:
11 Jun 2010.
*
Correspondence:
William Russ, UT Southwestern Medical Center, Pharmacology / Green Center for Systems Biology, Dallas, United States, russ@chop.swmed.edu