Myocilin

4WXQ, 4WXS, 4WXU465317926ENSG00000034971ENSMUSG00000026697Q99972O70624NM_000261NM_010865NP_000252NP_034995Myocilin, trabecular meshwork inducible glucocorticoid response, also known as MYOC, is a protein which in humans is encoded by the MYOC gene. Mutations in MYOC are a major cause of glaucoma. Myocilin, trabecular meshwork inducible glucocorticoid response, also known as MYOC, is a protein which in humans is encoded by the MYOC gene. Mutations in MYOC are a major cause of glaucoma. The cytogenetic location of human MYOC gene is on the long (q) arm of chromosome 1, specifically at position 24.3 (1q24.3). The gene’s molecular location starts at is 171,635,417 bp and ends at 171,652,63 bp on chromosome 1 (Annotation: GRCh38.p12) (assembly). Myocilin is a protein with a weight of 55 kDa (504 amino acid) and an overall acidic property is the first gene that has been linked to Primary Open Angle Glaucoma (POAG). The protein is made up of the two folding domains, the leucine zipper-like domain at the N-terminal and an olfactomedin-like domain at the C-terminal. The domain at the N-terminal is known to have 77.6% homology to the myosin heavy chain of Dictyostelium discoideum and 25% homology with the cardiac β-myosin heavy chain. The gene encodes three different exons, each consisting of different structural and functional domains. The N-terminal is encoded by exon 1 and contains the leucine zipper structural motif, which consists of 50 amino acid residues (117-169 amino acids). The motif is found on an α-helix, which enhances the binding of the protein. The name of the domain arises due to the occurrence of leucine as well as, arginine repeats periodically on the α-helix. The leucine zipper domain also contains the myocilin-myocilin interactions between amino acid residues 117-166. Exon 2 encodes the central region of the protein at amino acid residues 203-245 however, no structural or functional domains are found in this region. Exon 3 encodes the C-terminal of myocilin and has been found to contain the olfactomedin-like domain. The olfactomedin is an extracellular matrix protein with no defined role but is abundantly found in the olfactory neuroepithelium. In the myocilin protein, the domain consists of a single disulfide bond which connects two cysteine residues (245 and 433 amino acids). Myocilin is specifically located in the ciliary rootlet and basal body which connects to the cilium of photoreceptor cells in the rough endoplasmic reticulum. The intracellularly distributed protein is processed in the endoplasmic reticulum (ER) and in secreted into the aqueous humour. It is only imported into the trabecular meshwork of the mitochondria. In the extracellular space, it appears in the trabecular meshwork cells through an unconventional mechanism which is associated with exosome-like vesicles. Myocilin localises in the Golgi apparatus of corneal fibroblasts and Schlemm's canal endothelial cells. Several isoforms are produced due to post-translational modifications processes including, glycosylation and palmitoylation. The gene undergoes N-glycosylation at the Asn-Glu-Ser site (57–59 amino acids) and O-glycosylation throughout the protein at the Ser-Pro, Pro-Ser, Thr-Xaa-Xaa-Pro, Ser-Xaa-Xaa-Xaa-Pro sites. Myocilin also undergoes a proteolytic cleavage in the endoplasmic reticulum at residue Arg-226. The cleavage process is calcium dependant and results in two fragments. One fragment contains the C-terminal olfactomedin-like domain (35 kDa), and the other contains the N-terminal leucine zipper-like domain (20 kDa). MYOC encodes the protein myocilin. The precise function of myocilin is unknown, but it is normally secreted into the aqueous humor of the eye. MYOC mutations, which cause myocilin to accumulate in the cells of the trabecular meshwork are a common cause of glaucoma. Most MYOC mutations identified in glaucoma patients are heterozygous and are confined to the olfactomedin domain, which is encoded by exon 3.