title: Did myocilin evolve from two different primordial proteins?
abstract: OBJECTIVE
  Myocilin, a 57 kDa glycoprotein, has been of much interest because of its association with primary open-angle glaucoma, lack of understanding of its biological function, and sequence homology of its N- and C-termini with two distinctly different proteins, myosin and olfactomedin, respectively. In that context, the molecular evolution of myocilin was investigated.
  
  
  METHODS
  The human myocilin protein was used as query in sequence alignment program and the similar protein sequences were searched in the protein databases for different species. The secondary structure analysis of human myocilin and the prediction of disulfide bonded cysteine residues in the protein were done using PSIPRED and CYSPRED software, respectively. Presence of putative motifs in the protein sequences was determined using the ScanProsite tool with the option of including patterns with the high probability of occurrence. The phylogenetic analyses of human, mouse, rat, and bovine myocilin were done at the DNA Data Bank of Japan (DDBJ) server.
  
  
  RESULTS
  It was observed that while two different protein sequences from Drosophila melanogaster contained significant homology with either C-terminal or N-terminal of myocilin, a single protein from Xenopus laevis showed homology covering entire C-terminal and most of the N-terminal region of myocilin. These observations are noteworthy in the context of the previously reported homology of N-terminal domain of myocilin with a single protein (non-muscle myosin) in Dictyostelium discoideum, and C-terminal domain with a single protein (olfactomedin-like) in Caenorhabditis elegans, both representing lower organisms. Further, specific amino acids and putative functional motifs were observed to be conserved between the two sets of proteins having homology to two ends (N- and C-termini) of myocilin. At the secondary structure level, myocilin shows two distinctly different domains: (a) the N-terminal region is primarily a-helical type, and (b) the C-terminal region consists mostly of beta-sheet and turn.
  
  
  CONCLUSIONS
  These observations led to the hypothesis that during evolution myocilin might have resulted from fusion of genes for at least two different proteins with functional implications relevant to mammals. It is noteworthy that mutations in the myocilin gene, causal to Primary Open Angle Glaucoma, have only been detected in the first exon (corresponding to myosin like region) and the last exon (corresponding to olfactomedin domain) but not the region (exon 2) between the two domains. Phylogenetic analysis of mammalian myocilin revealed that rat and mouse myocilins demonstrate a closer relationship compared to its human or bovine homologues.
authors.affiliation: Indian Institute of Chemical Biology, Human Genetics & Genomics Division, Jadavpur, Kolkata, India.
authors.forename: Arijit
authors.initials: A
authors.lastname: Mukhopadhyay
authors.forename: Arnab
authors.initials: A
authors.lastname: Gupta
authors.forename: Saibal
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Keya
authors.initials: K
authors.lastname: Chaudhuri
authors.forename: Kunal
authors.initials: K
authors.lastname: Ray
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000235:genetics; D002417:Cattle; D003598:Cytoskeletal Proteins; D016208:Databases, Factual; D004023:Dictyostelium / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D019143:Evolution, Molecular; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D005902:Glaucoma, Open-Angle / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009218:Myosins / Q000235:genetics; D017433:Protein Structure, Secondary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis / Q000235:genetics; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D009218:Myosins; D000099179:Myocilin; C081451:olfactomedin