2kbs
From Proteopedia
Solution structure of harmonin PDZ2 in complex with the carboxyl tail peptide of cadherin23
Structural highlights
Disease[USH1C_HUMAN] Defects in USH1C are the cause of Usher syndrome type 1C (USH1C) [MIM:276904]; also known as Usher syndrome type I Acadian variety. USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa and sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness.[1] Defects in USH1C are the cause of deafness, autosomal recessive, 18A (DFNB18A) [MIM:602092]. A form of sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.[2] [CAD23_HUMAN] Defects in CDH23 are the cause of Usher syndrome type 1D (USH1D) [MIM:601067]. USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa and sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness.[3] [4] [5] [6] [7] [8] Defects in CDH23 are a cause of Usher syndrome type 1D/F (USH1DF) [MIM:601067]. USH1DF patients are heterozygous for mutations in CDH23 and PCDH15, indicating a digenic inheritance pattern.[9] Defects in CDH23 are the cause of deafness autosomal recessive type 12 (DFNB12) [MIM:601386]. DFNB12 is a form of sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.[10] [11] [12] [13] [14] [15] Function[USH1C_HUMAN] Required for normal development and maintenance of cochlear hair cell bundles. Anchoring/scaffolding protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing (By similarity). [CAD23_HUMAN] Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells. CDH23 is required for establishing and/or maintaining the proper organization of the stereocilia bundle of hair cells in the cochlea and the vestibule during late embryonic/early postnatal development. It is part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe hereditary hearing-vision loss disease Usher syndrome (USH) is caused by defects in several proteins, most of which form an integrated protein network called Usher interactome. Harmonin/Ush1C is a master scaffold in the assembly of the Usher protein complexes, because harmonin is known to bind to every protein in the Usher interactome. However, the biochemical and structural mechanism governing the Usher protein complex formation is largely unclear. Here, we report that the highly-conserved N-terminal fragment of harmonin (N-domain) immediately preceding its PDZ1 adopts an autonomously-folded domain. We discovered that the N-domain specifically binds to a short internal peptide fragment of the cadherin 23 cytoplasmic domain. The structures of the harmonin N-domain alone and in complex with the cadherin 23 internal peptide fragment uncovered the detailed binding mechanism of this interaction between harmonin and cadherin 23. We further elucidated the harmonin PDZ domain-mediated cadherin 23 binding by solving the structure of the second harmonin PDZ domain in complex with the cadherin 23 carboxyl tail. The multidentate binding mode between harmonin and cadherin 23 provides a structural and biochemical basis for the harmonin-mediated assembly of stable tip link complex in the auditory hair cells. Assembling stable hair cell tip link complex via multidentate interactions between harmonin and cadherin 23.,Pan L, Yan J, Wu L, Zhang M Proc Natl Acad Sci U S A. 2009 Mar 18. PMID:19297620[16] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Pan, L | Wu, L | Yan, J | Zhang, M | Alternative splicing | Calcium | Cell adhesion | Cell membrane | Coiled coil | Deafness | Disease mutation | Glycoprotein | Hearing | Membrane | Non-syndromic deafness | Phosphoprotein | Polymorphism | Protein complex | Retinitis pigmentosa | Sensory transduction | Structural protein-cell adhesion complex | Transmembrane | Usher syndrome | Vision
