title: Tracing the evolution of FERM domain of Kindlins.
abstract: Kindlin proteins represent a novel family of evolutionarily conserved FERM domain containing proteins (FDCPs) and are members of B4.1 superfamily. Kindlins consist of three conserved protein homologs in vertebrates: Kindlin-1, Kindlin-2 and Kindlin-3. All three homologs are associated with focal adhesions and are involved in Integrin activation. FERM domain of each Kindlin is bipartite and plays a key role in Integrin activation. A single ancestral Kindlin protein can be traced back to earliest metazoans, e.g., to Parazoa. This protein underwent multiple rounds of duplication in vertebrates, leading to the present Kindlin family. In this study, we trace phylogenetic and evolutionary history of Kindlin FERM domain with respect to FERM domain of other FDCPs. We show that FERM domain in Kindlin homologs is conserved among Kindlins but amount of conservation is less in comparison with FERM domain of other members in B4.1 superfamily. Furthermore, insertion of Pleckstrin Homology like domain in Kindlin FERM domain has important evolutionary and functional consequences. Important residues in Kindlins are traced and ranked according to their evolutionary significance. The structural and functional significance of high ranked residues is highlighted and validated by their known involvement in Kindlin associated diseases. In light of these findings, we hypothesize that FERM domain originated from a proto-Talin protein in unicellular or proto-multicellular organism and advent of multi-cellularity was accompanied by burst of FDCPs, which supported multi-cellularity functions required for complex organisms. This study helps in developing a better understanding of evolutionary history of FERM domain of FDCPs and the role of FERM domain in metazoan evolution.
authors.affiliation: KTH Royal Institute of Technology, School of Computer Science and Communication, Department of Computational Biology, 100 44 Stockholm, Sweden; Science for Life Laboratories, Karolinska Institute Science Park, 171 65 Solna, Sweden.
authors.forename: Raja Hashim
authors.initials: RH
authors.lastname: Ali
authors.affiliation: Quaid-i-Azam University, Department of Animal Sciences, Islamabad, Pakistan; Karolinska Institutet, Center for Biosciences, Department of Biosciences and Nutrition, Novum, 141 83 Huddinge, Sweden. Electronic address: ammadaslamkhan@gmail.com.
authors.forename: Ammad Aslam
authors.initials: AA
authors.lastname: Khan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019143:Evolution, Molecular; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA
chemical_list: D008565:Membrane Proteins
keywords: Evolutionary trace analysis; FERM domain; Focal adhesions; Kindlins; PH domain; Protein domain evolution