Proteopedia

2kbr

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Solution structure of harmonin N terminal domain in complex with a internal peptide of cadherin23Solution structure of harmonin N terminal domain in complex with a internal peptide of cadherin23

Structural highlights

2kbr is a 2 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:HARMONIN (HUMAN), Cadherin23 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

The 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 Also

References

  1. ↑ Verpy E, Leibovici M, Zwaenepoel I, Liu XZ, Gal A, Salem N, Mansour A, Blanchard S, Kobayashi I, Keats BJ, Slim R, Petit C. A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nat Genet. 2000 Sep;26(1):51-5. PMID:10973247 doi:10.1038/79171
  2. ↑ Ahmed ZM, Smith TN, Riazuddin S, Makishima T, Ghosh M, Bokhari S, Menon PS, Deshmukh D, Griffith AJ, Riazuddin S, Friedman TB, Wilcox ER. Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC. Hum Genet. 2002 Jun;110(6):527-31. Epub 2002 May 3. PMID:12107438 doi:10.1007/s00439-002-0732-4
  3. ↑ Bolz H, von Brederlow B, Ramirez A, Bryda EC, Kutsche K, Nothwang HG, Seeliger M, del C-Salcedo Cabrera M, Vila MC, Molina OP, Gal A, Kubisch C. Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat Genet. 2001 Jan;27(1):108-12. PMID:11138009 doi:10.1038/83667
  4. ↑ Astuto LM, Bork JM, Weston MD, Askew JW, Fields RR, Orten DJ, Ohliger SJ, Riazuddin S, Morell RJ, Khan S, Riazuddin S, Kremer H, van Hauwe P, Moller CG, Cremers CW, Ayuso C, Heckenlively JR, Rohrschneider K, Spandau U, Greenberg J, Ramesar R, Reardon W, Bitoun P, Millan J, Legge R, Friedman TB, Kimberling WJ. CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. Am J Hum Genet. 2002 Aug;71(2):262-75. Epub 2002 Jun 19. PMID:12075507 doi:10.1086/341558
  5. ↑ Ouyang XM, Yan D, Du LL, Hejtmancik JF, Jacobson SG, Nance WE, Li AR, Angeli S, Kaiser M, Newton V, Brown SD, Balkany T, Liu XZ. Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population. Hum Genet. 2005 Mar;116(4):292-9. Epub 2005 Jan 20. PMID:15660226 doi:10.1007/s00439-004-1227-2
  6. ↑ Zheng QY, Yan D, Ouyang XM, Du LL, Yu H, Chang B, Johnson KR, Liu XZ. Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Hum Mol Genet. 2005 Jan 1;14(1):103-11. Epub 2004 Nov 10. PMID:15537665 doi:ddi010
  7. ↑ Roux AF, Faugere V, Le Guedard S, Pallares-Ruiz N, Vielle A, Chambert S, Marlin S, Hamel C, Gilbert B, Malcolm S, Claustres M. Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%. J Med Genet. 2006 Sep;43(9):763-8. Epub 2006 May 5. PMID:16679490 doi:jmg.2006.041954
  8. ↑ Oshima A, Jaijo T, Aller E, Millan JM, Carney C, Usami S, Moller C, Kimberling WJ. Mutation profile of the CDH23 gene in 56 probands with Usher syndrome type I. Hum Mutat. 2008 Jun;29(6):E37-46. PMID:18429043 doi:10.1002/humu.20761
  9. ↑ Zheng QY, Yan D, Ouyang XM, Du LL, Yu H, Chang B, Johnson KR, Liu XZ. Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Hum Mol Genet. 2005 Jan 1;14(1):103-11. Epub 2004 Nov 10. PMID:15537665 doi:ddi010
  10. ↑ Astuto LM, Bork JM, Weston MD, Askew JW, Fields RR, Orten DJ, Ohliger SJ, Riazuddin S, Morell RJ, Khan S, Riazuddin S, Kremer H, van Hauwe P, Moller CG, Cremers CW, Ayuso C, Heckenlively JR, Rohrschneider K, Spandau U, Greenberg J, Ramesar R, Reardon W, Bitoun P, Millan J, Legge R, Friedman TB, Kimberling WJ. CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. Am J Hum Genet. 2002 Aug;71(2):262-75. Epub 2002 Jun 19. PMID:12075507 doi:10.1086/341558
  11. ↑ Roux AF, Faugere V, Le Guedard S, Pallares-Ruiz N, Vielle A, Chambert S, Marlin S, Hamel C, Gilbert B, Malcolm S, Claustres M. Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%. J Med Genet. 2006 Sep;43(9):763-8. Epub 2006 May 5. PMID:16679490 doi:jmg.2006.041954
  12. ↑ Bork JM, Peters LM, Riazuddin S, Bernstein SL, Ahmed ZM, Ness SL, Polomeno R, Ramesh A, Schloss M, Srisailpathy CR, Wayne S, Bellman S, Desmukh D, Ahmed Z, Khan SN, Kaloustian VM, Li XC, Lalwani A, Riazuddin S, Bitner-Glindzicz M, Nance WE, Liu XZ, Wistow G, Smith RJ, Griffith AJ, Wilcox ER, Friedman TB, Morell RJ. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am J Hum Genet. 2001 Jan;68(1):26-37. Epub 2000 Nov 21. PMID:11090341 doi:10.1086/316954
  13. ↑ de Brouwer AP, Pennings RJ, Roeters M, Van Hauwe P, Astuto LM, Hoefsloot LH, Huygen PL, van den Helm B, Deutman AF, Bork JM, Kimberling WJ, Cremers FP, Cremers CW, Kremer H. Mutations in the calcium-binding motifs of CDH23 and the 35delG mutation in GJB2 cause hearing loss in one family. Hum Genet. 2003 Feb;112(2):156-63. Epub 2002 Oct 29. PMID:12522556 doi:10.1007/s00439-002-0833-0
  14. ↑ Schultz JM, Yang Y, Caride AJ, Filoteo AG, Penheiter AR, Lagziel A, Morell RJ, Mohiddin SA, Fananapazir L, Madeo AC, Penniston JT, Griffith AJ. Modification of human hearing loss by plasma-membrane calcium pump PMCA2. N Engl J Med. 2005 Apr 14;352(15):1557-64. PMID:15829536 doi:10.1056/NEJMoa043899
  15. ↑ Wagatsuma M, Kitoh R, Suzuki H, Fukuoka H, Takumi Y, Usami S. Distribution and frequencies of CDH23 mutations in Japanese patients with non-syndromic hearing loss. Clin Genet. 2007 Oct;72(4):339-44. PMID:17850630 doi:10.1111/j.1399-0004.2007.00833.x
  16. ↑ Pan L, Yan J, Wu L, Zhang M. Assembling stable hair cell tip link complex via multidentate interactions between harmonin and cadherin 23. Proc Natl Acad Sci U S A. 2009 Mar 18. PMID:19297620
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