title: Novel domain architectures and functional determinants in atypical annexins revealed by phylogenomic analysis.
abstract: The fundamental cellular role and molecular interactions of annexins in vesicle trafficking and membrane remodeling remain to be further clarified in order to better understand and exploit their contributions to health and disease. We focused on distinctive features of atypical annexins from all domains of life using phylogenomic, molecular systematic and experimental approaches, to extend the current paradigm and better account for annexin diversity of structure, function and mechanistic role in membrane homeostasis. The analysis of gene duplications, organization of domain architectures and profile hidden Markov models of subfamily orthologs defined conserved structural features relevant to molecular interactions and functional divergence of seven family clades ANXA-G. Single domain annexins of bacteria, including cyanobacteria, were frequently coupled to enzymatic units conceivably related to membrane metabolism and remodeling. Multiple ANX domains (up to 20) and various distinct functional domains were observed in unique annexins. Canonical type 2 calcium binding ligands were well-preserved in roughly half of all ANX domains, but alternative structural motifs comprised of 'KGD', cysteine or tryptophan residues were prominently conserved in the same strategic interhelical loops. Selective evolutionary constraint, site-specific location and co-occurrence in all kingdoms identify alternative modes of fundamental binding interactions for annexins.
authors.affiliation: , Faculty of Medicine.
authors.forename: Maria-Pilar
authors.initials: MP
authors.lastname: Fernandez
authors.affiliation: , Faculty of Medicine.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia
authors.affiliation: , Faculty of Medicine.
authors.forename: Silvia
authors.initials: S
authors.lastname: Martin-Almedina
authors.affiliation: , Faculty of Medicine.
authors.forename: Reginald O
authors.initials: RO
authors.lastname: Morgan
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017302:Annexins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D023281:Genomics; D006801:Humans; D061986:MCF-7 Cells; D010802:Phylogeny; D000072417:Protein Domains
chemical_list: D017302:Annexins; D001426:Bacterial Proteins
keywords: 3D modeling; conserved motifs; functional determinants; membrane association; molecular phylogeny; profile hidden Markov models