Myocilin, trabecular meshwork inducible glucocorticoid response (TIGR), also known as MYOC, is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

which in humans is encoded by the ''MYOC''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. Mutations in ''MYOC'' are a major cause of

glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...

Gene location

The

cytogenetic Cytogenetics is essentially a branch of genetics, but is also a part of cell biology/cytology (a subdivision of human anatomy), that is concerned with how the chromosomes relate to cell behaviour, particularly to their behaviour during mitosis an ...

location of human ''MYOC''

is on the long (q) arm of

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...

, specifically at position 24.3 (1q24.3). The gene's molecular location starts at 171,635,417 bp and ends at 171,652,63 bp on

(Annotation: GRCh38.p12
(assembly).

Protein characteristics

Myocilin is a protein with a weight of 55 kDa (504

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

) and an overall acidic property is the first gene that has been linked to Primary Open Angle Glaucoma (POAG).

Protein structure

The protein is made up of the two folding domains, the leucine zipper-like

domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a partial function **Domain of holomorphy of a function * Do ...

at the

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

and an olfactomedin-like domain at the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

. The domain at the N-terminal is known to have 77.6% homology to the

myosin Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility. The first myosin ...

heavy chain of ''

Dictyostelium discoideum ''Dictyostelium discoideum'' is a species of soil-dwelling amoeba belonging to the phylum Amoebozoa, infraphylum Mycetozoa. Commonly referred to as slime mold, ''D. discoideum'' is a eukaryote that transitions from a collection of unicellular ...

'' 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 A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amin ...

structural motif In a polymer, chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common Biomolecular structure#Tertiary structure, three-dimensional structure that appears in a variety of different, evolutionarily unrel ...

, which consists of 50 amino acid residues (117-169 amino acids). The motif is found on an

α-helix The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ...

, which enhances the binding of the protein. The name of the domain arises due to the occurrence of

leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...

as well as,

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

repeats periodically on the

. 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 In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

bond which connects two

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

residues (245 and 433 amino acids).

Protein localisation

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 endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

. The intracellularly distributed protein is processed in the endoplasmic reticulum (ER) and in secreted into the

aqueous humour The aqueous humour is a transparent water-like fluid similar to plasma, but containing low protein concentrations. It is secreted from the ciliary body, a structure supporting the lens of the eyeball. It fills both the anterior and the poster ...

. It is only imported into the trabecular meshwork of the mitochondria. In the

extracellular space Extracellular space refers to the part of a multicellular organism outside the cells, usually taken to be outside the plasma membranes, and occupied by fluid. This is distinguished from intracellular space, which is inside the cells. The compos ...

, it appears in the trabecular meshwork cells through an unconventional mechanism which is associated with exosome-like vesicles. Myocilin localises in the

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...

of corneal fibroblasts and Schlemm's canal endothelial cells.

Protein processing

Several

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

are produced due to

post-translational modifications Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosom ...

processes including, glycosylation and

palmitoylation Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (''S''-palmitoylation) and less frequently to serine and threonine (''O''-palmitoylation) residues of proteins, which are typically lipid bilayer, memb ...

. 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 Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...

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).

Function

MYOC encodes the protein myocilin. The precise function of myocilin is unknown, but it is normally secreted into the

aqueous humor The aqueous humour is a transparent water-like fluid similar to plasma, but containing low protein concentrations. It is secreted from the ciliary body, a structure supporting the lens of the eyeball. It fills both the anterior and the posteri ...

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. Myocilin is believed to have a role in

cytoskeletal The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...

function. MYOC is expressed in many ocular tissues, including the

trabecular meshwork The trabecular meshwork is an area of tissue in the eye located around the base of the cornea, near the ciliary body, and is responsible for draining the aqueous humor from the eye via the anterior chamber (the chamber on the front of the ...

, and was revealed to be the trabecular meshwork glucocorticoid-inducible response protein (TIGR). The trabecular meshwork is a specialized eye tissue essential in regulating

intraocular pressure Intraocular pressure (IOP) is the fluid pressure inside the eye. Tonometry is the method eye care professionals use to determine this. IOP is an important aspect in the evaluation of patients at risk of glaucoma. Most tonometers are calibrated t ...

, and mutations in MYOC have been identified as the cause of hereditary juvenile-onset open-angle

. Scientific research has found the function of myocilin to be linked with other proteins, making it part of a

protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain. Protein c ...

. The isoform of the

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

protein, 1B1 (CYP1B1) has shown interaction with myocilin.

CYP1B1 Cytochrome P450 1B1 is an enzyme that in humans is encoded by the ''CYP1B1'' gene. Function CYP1B1 belongs to the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved i ...

is also found in several structures so the eye including, trabecular meshwork and the ciliary body.

Mutations and associated diseases

Differing mutations in the ''MYOC'' gene have been reported to associate with glaucoma 1, open angle (GLC1A) and glaucoma 3, primary congenital (GLC3A).

Glaucoma 1, open angle (GLC1A)

Glaucoma 1 is a form of primary open-angle glaucoma (POAG), which is characterized based on a specific pattern of defects in the

optic nerve In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual information from the retina to the brain. In humans, the optic nerve is derived fro ...

, thus causing visual defects. The disease causes an angle in the anterior chamber of the eye to be left open, which in turn causes the

to be increased. Although an increase in the intraocular pressure is a major factor for glaucoma, the disease can occur independently of the intraocular pressure. Furthermore, the damage done to the optical nerve has been classified as irreversible because no symptoms of the disease are apparent (

asymptomatic In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asy ...

) until its last stages.

Glaucoma 3, primary congenital (GLC3A)

Glaucoma 3 arises due to mutations in the distinct genetic loci of ''MYOC''. This mutation contributes to GLC3A through digenic inheritance with the

protein. The mutation gives rise to an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

form of primary congenital glaucoma (PCG). The disease initiates at birth or in early childhood due to the increase in intraocular pressure, large ocular globes (buphthalmos) and corneal edema. The progression of the disease causes defects in the trabecular meshwork and anterior chamber angle of the eye preventing the drainage from the

. ''Overall frequency of disease-causing mutations at MYOC in different races'':

Clinical significance

MYOC contains a signal sequence for secretion and is secreted into the aqueous humor of the eye by the trabecular meshwork. Mutations in MYOC are found in 4% of adult-onset primary open-angle glaucoma and >10% of juvenile-onset primary open-angle glaucoma. Overexpression or underexpression of MYOC does not cause glaucoma. However, the MYOC gene also contains a signal sequence, which is normally not functional, that directs intracellular proteins to

peroxisome A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen pero ...

s. Glaucoma-associated mutations activate that signal sequence and direct myocilin to peroxisomes, where they accumulate in the cell, instead of being secreted. Decreased secretion and increased accumulation appear to be the initial steps in myocilin-associated glaucoma. A study employing iterative pocket & ligand-similarity based approach to virtual ligand screening predicted small molecule binders for the olfactomedin domain of human myocilin. The predictions were subsequently assessed by differential scanning fluorimetry.

Interactions

MYOC has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with the following proteins: * OLFM3 * FN1 * NRCAM *GLDN * NFASC *

MYL2 Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC-2) also known as the regulatory light chain of myosin (RLC) is a protein that in humans is encoded by the ''MYL2'' gene. This cardiac ventricular RLC isoform is distinct from ...

* SFRP1 *FRZB *

FZD7 Frizzled-7 (Fd-7) is a protein that in humans is encoded by the ''FZD7'' gene. Members of the 'frizzled' gene family encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The FZD7 protein contains an N-terminal si ...

FZD10 Frizzled-10 (Fz-10) is a protein that in humans is encoded by the ''FZD10'' gene. Fz-10 has also been designated as CD350 (cluster of differentiation 350). Function This gene is a member of the frizzled Frizzled is a family of atypical G pr ...

FZD1 Frizzled-1 (Fz-1) is a protein that in humans is encoded by the ''FZD1'' gene. Function Members of the 'frizzled' gene family encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The FZD1 protein contains a si ...

WIF1 Wnt inhibitory factor 1 is a protein that in humans is encoded by the ''WIF1'' gene. WIF1 is a lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D ...

SNTA1 Alpha-1-syntrophin is a protein that in humans is encoded by the ''SNTA1'' gene. Alpha-1 syntrophin is a signal transducing adaptor protein and serves as a scaffold for various signaling molecules. Alpha-1 syntrophin contains a PDZ domain, two Ple ...

ERBB2 Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...

ERBB3 Receptor tyrosine-protein kinase erbB-3, also known as HER3 (human epidermal growth factor receptor 3), is a membrane bound protein that in humans is encoded by the ''ERBB3'' gene. ErbB3 is a member of the epidermal growth factor receptor (EGFR/ ...

SNCG Gamma-synuclein is a protein that in humans is encoded by the ''SNCG'' gene. Synuclein-gamma is a member of the synuclein family of proteins, which are believed to be involved in the pathogenesis of neurodegenerative diseases. High levels of SN ...