{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:08:57Z","timestamp":1791353337968,"version":"4.3.1"},"reference-count":29,"publisher":"National Academy of Sciences","issue":"9","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,3,2]]},"abstract":"<jats:p>The hereditary hearing-vision loss disease, Usher syndrome I (USH1), is caused by defects in several proteins that can interact with each other in vitro. Defects in USH1 proteins are thought to be responsible for the developmental and functional impairments of sensory cells in the retina and inner ear. Harmonin\/USH1C and Sans\/USH1G are two of the USH1 proteins that interact with each other. Harmonin also binds to other USH1 proteins such as cadherin 23 (CDH23) and protocadherin 15 (PCDH15). However, the molecular basis governing the harmonin and Sans interaction is largely unknown. Here, we report an unexpected assembly mode between harmonin and Sans. We demonstrate that the N-terminal domain and the first PDZ domain of harmonin are tethered by a small-domain C-terminal to PDZ1 to form a structural and functional supramodule responsible for binding to Sans. We discover that the SAM domain of Sans, specifically, binds to the PDZ domain of harmonin, revealing previously unknown interaction modes for both PDZ and SAM domains. We further show that the synergistic PDZ1\/SAM and PDZ1\/carboxyl PDZ binding-motif interactions, between harmonin and Sans, lock the two scaffold proteins into a highly stable complex. Mutations in harmonin and Sans found in USH1 patients are shown to destabilize the complex formation of the two proteins.<\/jats:p>","DOI":"10.1073\/pnas.0911385107","type":"journal-article","created":{"date-parts":[[2010,2,8]],"date-time":"2010-02-08T21:53:28Z","timestamp":1265666008000},"page":"4040-4045","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":102,"title":["The structure of the harmonin\/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins"],"prefix":"10.1073","volume":"107","author":[{"given":"Jing","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifeng","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuye","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,2,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/0-387-32442-9_49","article-title":"Molecular analysis of the supramolecular usher protein complex in the retina. Harmonin as the key protein of the Usher syndrome","volume":"572","author":"Reiners J","year":"2006","unstructured":"J Reiners, U Wolfrum, Molecular analysis of the supramolecular usher protein complex in the retina. Harmonin as the key protein of the Usher syndrome. Adv Exp Med Biol 572, 349\u2013353 (2006).","journal-title":"Adv Exp Med Biol"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"4593","DOI":"10.1242\/jcs.02636","article-title":"Usher I syndrome: Unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells","volume":"118","author":"El-Amraoui A","year":"2005","unstructured":"A El-Amraoui, C Petit, Usher I syndrome: Unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells. J Cell Sci 118, 4593\u20134603 (2005).","journal-title":"J Cell Sci"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1034\/j.1399-0004.2003.00109.x","article-title":"The molecular genetics of Usher syndrome","volume":"63","author":"Ahmed ZM","year":"2003","unstructured":"ZM Ahmed, S Riazuddin, ER Wilcox, The molecular genetics of Usher syndrome. Clin Genet 63, 431\u2013444 (2003).","journal-title":"Clin Genet"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"R262","DOI":"10.1093\/hmg\/ddl205","article-title":"Usher syndrome: Molecular links of pathogenesis, proteins and pathways","volume":"15","author":"Kremer H","year":"2006","unstructured":"H Kremer, E van Wijk, T Marker, U Wolfrum, R Roepman, Usher syndrome: Molecular links of pathogenesis, proteins and pathways. Hum Mol Genet 15, R262\u2013270, Spec No 2. (2006).","journal-title":"Hum Mol Genet"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.visres.2007.08.015","article-title":"Usher syndrome: Animal models, retinal function of Usher proteins, and prospects for gene therapy","volume":"48","author":"Williams DS","year":"2008","unstructured":"DS Williams, Usher syndrome: Animal models, retinal function of Usher proteins, and prospects for gene therapy. Vision Res 48, 433\u2013441 (2008).","journal-title":"Vision Res"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s00439-006-0304-0","article-title":"A novel gene for Usher syndrome type 2: Mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss","volume":"121","author":"Ebermann I","year":"2007","unstructured":"I Ebermann, et al., A novel gene for Usher syndrome type 2: Mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss. Hum Genet 121, 203\u2013211 (2007).","journal-title":"Hum Genet"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/hmg\/ddi031","article-title":"Interactions in the network of Usher syndrome type 1 proteins","volume":"14","author":"Adato A","year":"2005","unstructured":"A Adato, et al., Interactions in the network of Usher syndrome type 1 proteins. Hum Mol Genet 14, 347\u2013356 (2005).","journal-title":"Hum Mol Genet"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"6689","DOI":"10.1093\/emboj\/cdf689","article-title":"Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle","volume":"21","author":"Boeda B","year":"2002","unstructured":"B Boeda, et al., Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. EMBO J 21, 6689\u20136699 (2002).","journal-title":"EMBO J"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"14946","DOI":"10.1073\/pnas.232579599","article-title":"The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions","volume":"99","author":"Siemens J","year":"2002","unstructured":"J Siemens, et al., The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions. P Natl Acad Sci USA 99, 14946\u201314951 (2002).","journal-title":"P Natl Acad Sci USA"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1093\/hmg\/ddg051","article-title":"Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin","volume":"12","author":"Weil D","year":"2003","unstructured":"D Weil, et al., Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin. 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Neuron 62, 375\u2013387 (2009).","journal-title":"Neuron"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/79171","article-title":"A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C","volume":"26","author":"Verpy E","year":"2000","unstructured":"E Verpy, et al., A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. 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Nat Struct Mol Biol 12, 722\u2013728 (2005).","journal-title":"Nat Struct Mol Biol"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S0969-2126(03)00052-2","article-title":"PDZ tandem of human syntenin: Crystal structure and functional properties","volume":"11","author":"Kang BS","year":"2003","unstructured":"BS Kang, et al., PDZ tandem of human syntenin: Crystal structure and functional properties. Structure 11, 459\u2013468 (2003).","journal-title":"Structure"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1126\/science.1144592","article-title":"PDZ domain binding selectivity is optimized across the mouse proteome","volume":"317","author":"Stiffler MA","year":"2007","unstructured":"MA Stiffler, et al., PDZ domain binding selectivity is optimized across the mouse proteome. Science 317, 364\u2013369 (2007).","journal-title":"Science"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1007\/s00109-005-0719-4","article-title":"A novel D458V mutation in the SANS PDZ binding motif causes atypical Usher syndrome","volume":"83","author":"Kalay E","year":"2005","unstructured":"E Kalay, et al., A novel D458V mutation in the SANS PDZ binding motif causes atypical Usher syndrome. J Mol Med 83, 1025\u20131032 (2005).","journal-title":"J Mol Med"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1136\/jmg.2006.041954","article-title":"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%","volume":"43","author":"Roux AF","year":"2006","unstructured":"AF Roux, et al., 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 43, 763\u2013768 (2006).","journal-title":"J Med Genet"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1034\/j.1399-0004.2003.00058.x","article-title":"The contribution of USH1C mutations to syndromic and non-syndromic deafness in the UK","volume":"63","author":"Blaydon DC","year":"2003","unstructured":"DC Blaydon, et al., The contribution of USH1C mutations to syndromic and non-syndromic deafness in the UK. Clin Genet 63, 303\u2013307 (2003).","journal-title":"Clin Genet"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1107\/S0907444903028956","article-title":"Likelihood-enhanced fast rotation functions","volume":"60","author":"Storoni LC","year":"2004","unstructured":"LC Storoni, AJ McCoy, RJ Read, Likelihood-enhanced fast rotation functions. Acta Crystallogr D 60, 432\u2013438 (2004).","journal-title":"Acta Crystallogr D"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0911385107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T03:14:36Z","timestamp":1654571676000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0911385107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,2,8]]},"references-count":29,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2010,3,2]]}},"alternative-id":["10.1073\/pnas.0911385107"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0911385107","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,2,8]]},"assertion":[{"value":"2010-02-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}