Harmonine (protein)
| Harmonine (protein) | ||
|---|---|---|
| Properties of human protein | ||
| Mass / length primary structure | 552 amino acids | |
| Isoforms | 4th | |
| Identifier | ||
| Gene name | USH1C | |
| External IDs | ||
Harmonine is a scaffold protein that occurs in almost all cells . It is involved in the formation of specific protein complexes , especially with cell adhesion molecules in sensory cells . Mutations in the harmonin gene cause a form of Usher syndrome , the most common cause of hereditary blind deafness, but also recessive, autosomal and nonsyndromic deafness ( DFNB18 ). The gene for harmonin was originally identified as an autoimmune antigen in both colon cancer patients and in cases of X-chromosome-linked autoimmune enteropathy (AIE). As a result, the human isoform harmonin a1 is sometimes also referred to in the literature by the names PDZ-73 or AIE-75 .
Due to alternative splicing , harmonine occurs in several isoforms. The resulting isoforms of harmonine are characterized by their protein domains and are accordingly divided into three isoform subtype groups a, b and c.
construction
The harmonine isoforms have two to three so-called PDZ domains as an outstanding feature . Proteins that contain PDZ domains are usually in vivo as so-called “scaffold proteins”, that is, framework proteins, the basis for the organization of larger protein complexes in specific, subcellular compartments. Anticipating such a framework function also for Harmonin, this was named after the Greek word “ harmonia ” (ie “unification”, “unity”), which is derived from “ harmozein ” (= fit together). All harmonine isoforms have two PDZ domains (PDZ-1 and PDZ-2) at the N-terminal section. Harmonin a and b have another PDZ domain at the C-terminal end (PDZ-3).
Behind the second PDZ domain there is a coiled coil domain with an unknown function for all isoforms . Your main task is probably to define the distances between two points.
Harmonin b has a second, somewhat shorter coiled-coil domain, followed by a PST region. The letters PST stand for the amino acids proline , serine and threonine , which are more common in this region. It has been shown that this PST region can bundle fibrular actin and also protect against cleaving substances.
Expression
Harmonine is expressed in a large number of tissues and exists in various isoforms, which are created by alternative splicing of the product of the USH1C gene . In humans, this gene is located on the gene locus 11p15.2-p14. It consists of 20 constitutive exons and eight alternative exons, which means that at least nine harmonin isoforms can be expressed. The resulting isoforms of harmonine are characterized by their protein domains and are accordingly divided into three isoform subtype groups a, b and c. The isoforms are expressed in a tissue-specific manner, for example harmonin b occurs only in photoreceptor cells of the retina and in hair cells of the inner ear .
function
Harmonine interacts with a wide variety of proteins. In the first place, harmonin interacts with other Usher syndrome proteins: Myosin VIIa , SANS , Usherin and NBC3 bind to PDZ-1 ; Cadherin 23 and Protocadherin 15 bind to PDZ-2 . The scaffold protein harmonin thus connects the individual Usher syndrome proteins and should thus occupy a key position, as it can also interact with actin. Harmonine can therefore establish a connection between the cytoskeleton and membrane proteins. It is assumed that harmonine has an important role in the membrane positioning of these proteins at synapses and stimulus-absorbing structures of sensory cells. These complexes could be involved in neurotransmission and synaptic plasticity.
The protein HARP (“ Harmonin-interacting Ankyrin Repeat-containing Protein ”), a protein very similar to SANS, which occurs in the kidneys and pancreas, also binds to the first PDZ domain . A protein called MCC2 (“ Mutated in Colon Cancer-2 ”), a protein with great homology to the tumor suppressor MCC, from which it got its name, and the GTPase regulator DOCK4, also interacts with PDZ-1 . These interactions, which are presumably unrelated to Usher syndrome, point to the other functions of harmonin in tissues that are not affected by Usher syndrome. Here too, the role as a scaffold protein should be given.
literature
- C. Petit: Usher syndrome: from genetics to pathogenesis. Annu.Rev.Genomics Hum.Genet. 2001 (2): 271-297 PMID 11701652
- J. Reiners et al .: Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Exp Eye Res. 2006; 83 (1): 97-119 PMID 16545802