Usher 1C
- OMIM: 605242
- UniProt: Q9Y6N9
Harmonin is a scaffolding protein, which is found almost ubiquitously in all cells. It is involved in the formation of specific protein complexes, especially cell adhesion molecules in the sense cells. Mutations in the gene of Harmonin cause a form of Usher syndrome, the most common cause of hereditary deafness blind, but also a recessive, autosomal and nichtsyndromische deafness ( DFNB18 ). The gene for Harmonin was originally identified as an autoimmune antigen in both cancer patients and in cases of X - chromosome -linked autoimmune enteropathy (AIE ). Thus, the human isoform Harmonin a1 is sometimes referred to in the literature with the name PDZ -73, respectively AIE -75.
Due to alternative splicing Harmonin comes in several isoforms. The resulting isoforms Harmonin be characterized by their protein domains and correspondingly divided into three isoform - subtype a, b and c.
Construction
The Harmonin isoforms possess an outstanding feature two to three so-called PDZ domains. Proteins containing PDZ domains are usually in vivo and so-called " protein scaffold " that is, scaffold proteins, based on the organization of large protein complexes to specific subcellular compartments. Such scaffolding function anticipation for Harmonin, this after the Greek word " harmonia " (ie, " agreement ", " harmony " ) was named that " harmozein " of ( = match) is derived. Harmonin all isoforms have at the N -terminal portion of two PDZ domains ( PDZ and PDZ -1 -2). Harmonin a and b do not have a more PDZ domain to the C -terminal end ( PDZ -3).
Behind the second PDZ domain located in all isoforms of a coiled- coil domain of unknown function. Their main task is probably to define distances between two points.
A second slightly shorter coiled- coil domain has Harmonin b, followed by a PST region. The letters stand for the amino acids proline PST, serine and threonine, which occur increasingly in this region. It has been shown that this PST region may combine fibruläres actin and also protects against cleaving substances.
Expression
Harmonin is expressed in many tissues and thereby exists in different isoforms that arise by alternative splicing of the product from USH1C gene. This gene is located in humans on the gene locus 11p15.2 - p14. It consists of 20 constitutive exons and eight alternative exons, which at least nine Harmonin isoforms can be expressed. The resulting isoforms Harmonin be characterized by their protein domains and correspondingly divided into three isoform - subtype a, b and c. The isoforms are expressed gewebespezisch, for example, comes Harmonin b only in photoreceptor cells of the retina and hair cells of the inner ear before.
Function
Harmonin interacts with a variety of proteins. In the first place Harmonin interacts with other Usher syndrome proteins: PDZ -1 binds to myosin VIIa, SANS, Usherin and NBC3; PDZ -2 binds to cadherin 23 and protocadherin 15 The scaffold protein Harmonin therefore connects the individual Usher syndrome proteins and is likely to play a key role since it can also interact with actin. Harmonin can thus establish a link between the cytoskeleton and membrane proteins. It is believed that Harmonin has an important role in the membrane positioning of these proteins at synapses and charming receiving structures of sensory cells. These complexes may be involved in neurotransmission, and synaptic plasticity.
Also on the first PDZ domain binds the protein HARP ( " Harmonin -interacting ankyrin repeat -containing protein" ), a protein with high similarity to SANS, which occurs in the kidney and pancreas. Using PDZ- 1 also interacts a protein called MCC2 ( " Mutated in Colon Cancer- 2 "), a protein with high homology to the tumor suppressor MCC, from whom it received its name as well as the GTPase regulator DOCK4. These interactions which presumably have no connection with the Usher syndrome, point to the other functions of Harmonin in tissues which are not affected by Usher syndrome. Here, too, should be given as a scaffold protein that role.