Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1763, Issue 11, Pages 1238-1249Publisher
ELSEVIER
DOI: 10.1016/j.bbamcr.2006.09.028
Keywords
computational biology; functional determinant; hidden Markov model (HMM); membrane-binding mechanism; molecular evolution; receptor docking
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Calcium-binding proteins regulate ion metabolism and vital signalling pathways in all living organisms. Our aim is to rationalize the molecular basis of their function by studying their evolution using computational biology techniques. Phylogenctic analysis is of primary importance for classifying cognate orthologs; profile hidden Markov models (HMM) of individual subfamilies discern functionally relevant sites by conservation probability analysis; and 3-dimensional structures display the integral protein in context. The major classifications of calcium-binding proteins, viz. EF-hand, C2 and ANX, exhibit structural diversity in their HMM fingerprints at the subfamily level, with functional consequences for protein conformation, exposure of receptor interaction sites and/or binding to membrane phospholipids. Calmodulin, S100 and annexin families were characterized in Petromyzon marinus (sea lamprey) to document genome duplication and gene creation events during the key evolutionary transition to primitive vertebrates. Novel annexins from diverse organisms revealed calcium-binding domains with accessory structural features that define their unique molecular fingerprints, protein interactivity and functional specificity. These include the first single-domain, bacterial annexin in Cytophaga hutchinsonii, the 21 tetrad annexins from the unicellular protist Giardia intestinalis, an ancestor to land plant annexins from the green alga Ostreococcus lucimarinus, invertebrate octad annexins and a critical polymorphism in human ANXA7. Receptor docking models supported the hypothesis of a potential interaction between annexin and C2 domains as a propitious mechanism for ensuring membrane translocation during signal transduction. (c) 2006 Elsevier B.V. All rights reserved.
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