Deciphering function and mechanism of calcium-binding proteins from their evolutionary imprints

Abstract

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. Phylogenetic 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.

Structural and lipid-binding characterization of human annexin A13a reveals strong differences with its long A13b isoform

“…They are expressed by all living organisms, from protists to higher eukaryotes and plants, but with the exception of bacteria. However, the group of Fernandez and Morgan first reported the presence of a gene coding for a single domain annexin in the bacteria Cytophaga hutchinsonii, although the protein is not expressed (Morgan et al, 2006) and a broader survey of bacterial genomes has identified around 30 annexin homologs, including single-domain and multi-domain annexins in 17 bacterial species (Kodavali et al, 2014).…”

Zea mays Annexins Modulate Cytosolic Free Ca2+ and Generate a Ca2+-Permeable Conductance

“…Annexins form a multigene, multifunctional family of amphipathic proteins with a broad taxonomic distribution covering prokaryotes, fungi, protists, plants, and higher vertebrates (Gerke and Moss, 2002;Morgan et al, 2004Morgan et al, , 2006. Found in all plants studied to date and in all organs, these small (32 to 42 kD) proteins can comprise up to 0.1% of total plant cell protein (Delmer and Potikha, 1997;Clark et al, 2001;Moss and Morgan, 2004;Mortimer et al, 2008).…”

Arabidopsis Annexin1 Mediates the Radical-Activated Plasma Membrane Ca2+- and K+-Permeable Conductance in Root Cells

“…Hence, an Arabidopsis annexin could be responsible for forming the PM OH _ -activated Ca 2+ conductance. Annexins are membrane binding proteins found in pro-and eukaryotes (Morgan et al, 2006). Several animal annexins have been reported to function in vitro as Ca 2+ channels, including vertebrate annexins A1, 2, 5 to 7, and 12 (Burger et al, 1994;Liemann et al, 1996;Kourie and Wood, 2000).…”