| Structural highlights
4wxu is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.092Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
MYOC_HUMAN Congenital glaucoma;Juvenile glaucoma. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. MYOC mutations may contribute to GLC3A via digenic inheritance with CYP1B1 and/or another locus associated with the disease (PubMed:15733270).[1]
Function
MYOC_HUMAN Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration. Promotes substrate adhesion, spreading and formation of focal contacts. Negatively regulates cell-matrix adhesion and stress fiber assembly through Rho protein signal transduction. Modulates the organization of actin cytoskeleton by stimulating the formation of stress fibers through interactions with components of Wnt signaling pathways. Promotes cell migration through activation of PTK2 and the downstream phosphatidylinositol 3-kinase signaling. Plays a role in bone formation and promotes osteoblast differentiation in a dose-dependent manner through mitogen-activated protein kinase signaling. Mediates myelination in the peripheral nervous system through ERBB2/ERBB3 signaling. Plays a role as a regulator of muscle hypertrophy through the components of dystrophin-associated protein complex. Involved in positive regulation of mitochondrial depolarization. Plays a role in neurite outgrowth. May participate in the obstruction of fluid outflow in the trabecular meshwork.[2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
Olfactomedin (OLF) domain-containing proteins play roles in fundamental cellular processes and have been implicated in disorders ranging from glaucoma, cancers and inflammatory bowel disorder, to attention deficit disorder and childhood obesity. We solved crystal structures of the OLF domain of myocilin (myoc-OLF), the best studied such domain to date. Mutations in myoc-OLF are causative in the autosomal dominant inherited form of the prevalent ocular disorder glaucoma. The structures reveal a new addition to the small family of five-bladed beta-propellers. Propellers are most well known for their ability to act as hubs for protein-protein interactions, a function that seems most likely for myoc-OLF, but they can also act as enzymes. A calcium ion, sodium ion and glycerol molecule were identified within a central hydrophilic cavity that is accessible via movements of surface loop residues. By mapping familial glaucoma-associated lesions onto the myoc-OLF structure, three regions sensitive to aggregation have been identified, with direct applicability to differentiating between neutral and disease-causing non-synonymous mutations documented in the human population worldwide. Evolutionary analysis mapped onto the myoc-OLF structure reveals conserved and divergent regions for possible overlapping and distinctive functional protein-protein or protein-ligand interactions across the broader OLF domain family. While deciphering the specific normal biological functions, ligands and binding partners for OLF domains will likely continue to be a challenging long-term experimental pursuit, atomic detail structural knowledge of myoc-OLF is a valuable guide for understanding the implications of glaucoma-associated mutations and will help focus future studies of this biomedically important domain family.
Structural basis for misfolding in myocilin-associated glaucoma.,Donegan RK, Hill SE, Freeman DM, Nguyen E, Orwig SD, Turnage KC, Lieberman RL Hum Mol Genet. 2015 Apr 15;24(8):2111-24. doi: 10.1093/hmg/ddu730. Epub 2014 Dec , 18. PMID:25524706[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kaur K, Reddy AB, Mukhopadhyay A, Mandal AK, Hasnain SE, Ray K, Thomas R, Balasubramanian D, Chakrabarti S. Myocilin gene implicated in primary congenital glaucoma. Clin Genet. 2005 Apr;67(4):335-40. PMID:15733270 doi:http://dx.doi.org/10.1111/j.1399-0004.2005.00411.x
- ↑ Sakai H, Shen X, Koga T, Park BC, Noskina Y, Tibudan M, Yue BY. Mitochondrial association of myocilin, product of a glaucoma gene, in human trabecular meshwork cells. J Cell Physiol. 2007 Dec;213(3):775-84. PMID:17516541 doi:http://dx.doi.org/10.1002/jcp.21147
- ↑ Shen X, Koga T, Park BC, SundarRaj N, Yue BY. Rho GTPase and cAMP/protein kinase A signaling mediates myocilin-induced alterations in cultured human trabecular meshwork cells. J Biol Chem. 2008 Jan 4;283(1):603-12. Epub 2007 Nov 5. PMID:17984096 doi:http://dx.doi.org/10.1074/jbc.M708250200
- ↑ Goldwich A, Scholz M, Tamm ER. Myocilin promotes substrate adhesion, spreading and formation of focal contacts in podocytes and mesangial cells. Histochem Cell Biol. 2009 Feb;131(2):167-80. doi: 10.1007/s00418-008-0518-4. Epub, 2008 Oct 15. PMID:18855004 doi:http://dx.doi.org/10.1007/s00418-008-0518-4
- ↑ Kwon HS, Lee HS, Ji Y, Rubin JS, Tomarev SI. Myocilin is a modulator of Wnt signaling. Mol Cell Biol. 2009 Apr;29(8):2139-54. doi: 10.1128/MCB.01274-08. Epub 2009 Feb, 2. PMID:19188438 doi:http://dx.doi.org/10.1128/MCB.01274-08
- ↑ Koga T, Shen X, Park JS, Qiu Y, Park BC, Shyam R, Yue BY. Differential effects of myocilin and optineurin, two glaucoma genes, on neurite outgrowth. Am J Pathol. 2010 Jan;176(1):343-52. doi: 10.2353/ajpath.2010.090194. Epub 2009, Dec 3. PMID:19959812 doi:http://dx.doi.org/10.2353/ajpath.2010.090194
- ↑ Kwon HS, Tomarev SI. Myocilin, a glaucoma-associated protein, promotes cell migration through activation of integrin-focal adhesion kinase-serine/threonine kinase signaling pathway. J Cell Physiol. 2011 Dec;226(12):3392-402. doi: 10.1002/jcp.22701. PMID:21656515 doi:http://dx.doi.org/10.1002/jcp.22701
- ↑ Kwon HS, Johnson TV, Tomarev SI. Myocilin stimulates osteogenic differentiation of mesenchymal stem cells through mitogen-activated protein kinase signaling. J Biol Chem. 2013 Jun 7;288(23):16882-94. doi: 10.1074/jbc.M112.422972. Epub 2013, Apr 29. PMID:23629661 doi:http://dx.doi.org/10.1074/jbc.M112.422972
- ↑ Kwon HS, Johnson TV, Joe MK, Abu-Asab M, Zhang J, Chan CC, Tomarev SI. Myocilin mediates myelination in the peripheral nervous system through ErbB2/3 signaling. J Biol Chem. 2013 Sep 13;288(37):26357-71. doi: 10.1074/jbc.M112.446138. Epub, 2013 Jul 29. PMID:23897819 doi:http://dx.doi.org/10.1074/jbc.M112.446138
- ↑ Donegan RK, Hill SE, Freeman DM, Nguyen E, Orwig SD, Turnage KC, Lieberman RL. Structural basis for misfolding in myocilin-associated glaucoma. Hum Mol Genet. 2015 Apr 15;24(8):2111-24. doi: 10.1093/hmg/ddu730. Epub 2014 Dec , 18. PMID:25524706 doi:http://dx.doi.org/10.1093/hmg/ddu730
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