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

Summary: 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
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 func-
tional 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 par-
ticular, it elucidates the selective forces creating coevolution among protein sites.


Source: Atchley, William R.- Department of Genetics, North Carolina State University


Collections: Biology and Medicine