Physiological function of myocilin and its role in the pathogenesis of glaucoma in the trabecular meshwork (Review)

Abstract

Myocilin is highly expressed in the trabecular meshwork (TM), which plays an important role in the regulation of intraocular pressure (IOP). Myocilin abnormalities may cause dysfunction of the TM, potentially leading to increased IOP. High IOP is a well‑known primary risk factor for glaucoma. Myocilin mutations are common among glaucoma patients, and they are implicated in juvenile‑onset open‑angle glaucoma (JOAG) and adult‑onset primary open‑angle glaucoma (POAG). Aggregation of aberrant mutant myocilins is closely associated with glaucoma pathogenesis. The aim of the present review was to discuss the recent findings regarding the major physiological functions of myocilin, such as intra‑ and extracellular proteolytic processes. We also aimed to discuss the risk factors associated with myocilin and the development of glaucoma, such as misfolded/mutant myocilin, imbalance of myocilin and extracellular proteins, and instability of mutant myocilin associated with temperature. Finally, we further outlined certain issues that are yet to be resolved, which may represent the basis for future studies on the role of myocilin in glaucoma.

Figure 1

Structure of myocilin and pathogenic mutations localized in exons 1-3 (33). Three modules encoded by exons 1-3 approximately coincide with the N-terminus, LINK and C-terminus. SP, signal peptide; LINK, linker domain.

Figure 2

Proteolytic process of myocilin through calpain II (40). The proteo-lytic processing of myocilin is carried out by calpain II in the endoplasmic reticulum, producing two myocilin fragments: One containing LZ that is intracellularly retained and another containing OLF that is extracellularly secreted. Some full-length myocilins with LZ and OLF are also secreted. LINK contains the cleavage site. LZ, leucine zippers; OLF, olfactomedin; LINK, linker domain.

Figure 3

Interactions of myocilin with extracellular matrix proteins (laminin and fibronectin) and matricellular proteins (SPARC and hevin) (34). Homoaggregates of myocilin monomers covalently interact through disulfide bonds (short red lines) within LZ (12). Myocilin complexes interact by noncovalent bonds (grey dashed lines) in N-terminus (rectangle linked to the blue oval). Full-length myocilins non-covalently (black dots) interact with the extracellular calcium binding domains (brick pattern) of SPARC and hevin through OLF (blue oval). Interacting fashion of myocilin with laminin and fibronectin could be similar to that of SPARC and hevin. SPARC, secreted protein acidic and rich in cysteine; LZ, leucine zippers; OLF, olfactomedin.

Figure 4

Co-aggregation of Grp94 with mutant/misfolded myocilin (80). Grp94, glucose-regulated protein 94.

Figure 5

Structure of myocilin (108,117). (A) The N-terminus has a Y-shaped parallel (117). (B) The crystal of myocilin-OLF is a five-bladed β-propeller, and each blade is composed of four antiparallel β-strands, arranged radically around a central water-filled cavity (108). The blades in OLF are notably asymmetric. Nearly half of the toroid-shaped molecule is occupied by blades D and E. The myocilin-OLF propeller has five blades (A, B, C, D and E). A disulfide bond and calcium-binding site are located at the bottom face of the propeller, and a single disulfide bond is observed between Cys433 located within Loop D-15/D-16 and Cys245 at the N-terminus prior to the start of E-1. Tyr 437 further stabilizes the region near the single disulfide bond. Unlike other amyloid-like proteins (120), the effect of disulfide bonds on the stability of wild-type myocilin is not significant.