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MBE Advance Access originally published online on April 27, 2005
Molecular Biology and Evolution 2005 22(7):1627-1634; doi:10.1093/molbev/msi157
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© The Author 2005. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org

Research Article

Networks of Coevolving Sites in Structural and Functional Domains of Serpin Proteins

Michael J. Buck1 and William R. Atchley

Department of Genetics and The Center for Computational Biology, North Carolina State University

E-mail: mjbuck{at}bio.unc.edu.

Amino acids do not occur randomly in proteins; rather, their occurrence at any given site is strongly influenced by the amino acid composition at other sites, the structural and functional aspects of the region of the protein in which they occur, and the evolutionary history of the protein. The goal of our research study is to identify networks of coevolving sites within the serpin proteins (serine protease inhibitors) and classify them as being caused by structural-functional constraints or by evolutionary history. To address this, a matrix of pairwise normalized mutual information (NMI) values was computed among amino acid sites for the serpin proteins. The NMI matrix was partitioned into orthogonal patterns of amino acid variability by factor analysis. Each common factor pattern was interpreted as having phylogenetic and/or structural-functional explanations. In addition, we used a bootstrap factor analysis technique to limit the effects of phylogenetic history on our factor patterns. Our results show an extensive network of correlations among amino acid sites in key functional regions (reactive center loop, shutter, and breach). Additionally, we have discovered long-range coevolution for packed amino acids within the serpin protein core. Lastly, we have discovered a group of serpin sites which coevolve in the hydrophobic core region (s5B and s4B) and appear to represent sites important for formation of the "native" instead of the "latent" serpin structure. This research provides a better understanding on how protein structure evolves; in particular, it elucidates the selective forces creating coevolution among protein sites.

Key Words: serpin • factor analysis • coevolution • covariation • protein structure • mutual information


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W. R. Atchley and J. Zhao
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Mol. Biol. Evol., January 1, 2007; 24(1): 192 - 202.
[Abstract] [Full Text] [PDF]


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