Obscurin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''OBSCN''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Obscurin belongs to the family of giant sarcomeric signaling proteins that includes

titin Titin (; also called connectin) is a protein that in humans is encoded by the ''TTN'' gene. The protein, which is over 1 μm in length, functions as a molecular spring that is responsible for the passive elasticity of muscle. It comprises 2 ...

and

nebulin Nebulin is an actin-binding protein which is localized to the thin filament of the sarcomeres in skeletal muscle. Nebulin in humans is coded for by the gene ''NEB''. It is a very large protein (600–900 kDa) and binds as many as 200 actin monome ...

. Obscurin is expressed in

cardiac The heart is a muscular organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrients to the tissu ...

and

skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

, and plays a role in the organization of

myofibril A myofibril (also known as a muscle fibril or sarcostyle) is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as Skeletal muscle#Skeletal muscle cells, muscle fibers, and these cells contain ...

s during

sarcomere A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal striated muscle, Skeletal muscles are composed of tubular ...

assembly. A mutation in the ''OBSCN'' gene has been associated with

hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which muscle tissues of the heart become thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ...

and altered obscurin protein properties have been associated with other muscle diseases.

Structure

Human obscurin may exist as multiple splice variants of approximately 720

kDa The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...

, however the full-length nature of only one has been described to date. Obscurin is expressed in cardiac and skeletal muscle. The obscurin gene spans more than 150 kb, contains over 80

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s. The encoded protein contains 68 Ig domains, 2 fibronectin domains, 1 IQ calmodulin-binding motif, 1

RhoGEF domain RhoGEF domain describes two distinct structural domains with guanine nucleotide exchange factor (GEF) activity to regulate small GTPases in the Rho family. Rho small GTPases are inactive when bound to GDP but active when bound to GTP; RhoGEF ...

with an associated

PH domain Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phosph ...

, and 2 serine-threonine kinase domains. The dominant location of obscurin in mature

s is at the sarcomeric M-band.

Titin Titin (; also called connectin) is a protein that in humans is encoded by the ''TTN'' gene. The protein, which is over 1 μm in length, functions as a molecular spring that is responsible for the passive elasticity of muscle. It comprises 2 ...

, obscurin, obscurin-like-1 and

myomesin Myomesin is a protein Protein family, family found in the M-line of the sarcomere structure. Myomesin has various forms throughout the body in Striated muscle tissue, striated muscles with specialized functions. This includes both Slow twitch fiber ...

form a ternary complex at sarcomeric M-bands that is critical for

mechanics.

Function

Obscurin belongs to the family of giant sarcomeric signaling proteins that includes

and

, and may have a role in the organization of

s during assembly and may mediate interactions between the

sarcoplasmic reticulum The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kep ...

and

s. Obscurin is the major

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

for small ankyrin 1 (sANK1), a sarcoplasmic reticular protein, and the scaffolding function of obscurin appears to prevent degradation of sANK1. These data indicate that obscurin serves as a signaling link between the sarcomeric and sarcoplasmic reticular domains, Obscurin plays a role in the formation of new

s during

assembly. specifically, at the sarcomeric periphery where sites of initiation and progression of myofibrilogenesis lie. Obscurin appears to be necessary for the proper incorporation of

myosin Myosins () are a Protein family, family of motor proteins (though most often protein complexes) best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are adenosine triphosphate, ATP- ...

filaments into

s and in the assembly of A-bands. Moreover, the kinase domains of obscurin are enzymatically active and appear to be involved in the regulation of cell adhesion.

Clinical significance

Obscurin has been shown to exhibit a disease-related isoform switch in patients with

dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. C ...

. An obscurin mutation Arg4344 Gln was identified in patients with

, which disrupted binding of obscurin to the Z9-Z10 domains of

. A later study, however, was not able to reproduce this effect. Due to lack of mechanistic evidence and the high prevalence among African Americans, the Arg4344Gln variant is currently not considered to be pathogenic. Mutations found the gene encoding

in patients with limb-girdle muscular dystrophy 2J or Salih myopathy decrease the ability of

to bind obscurin, suggesting that this may be causative in disease manifestation.

Interactions

Obscurin has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...

with

, specifically, with the Novex-3 of

, a 6.5 kb

located upstream of the

-specific N2B

. The C-terminal region of Obscurin interacts with the cytoplasmic domain of small ankyrin 1 and with the exon 43' region of ankyrin B. The Ig3 of obscurin binds

at the linker between My4 and My5.

Structure

Function

Clinical significance

Interactions

References

Further reading