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Here, in search of molecular origins for ARHL, we dissect the conformational behavior of cadherin-23 along with the mutant S47P that progresses the hearing loss drastically. Using an array of experimental and computational approaches, we highlight a lower thermodynamic stability, significant weakening in the hydrogen-bond network and inter-residue correlations among \u03b2-strands, due to the S47P mutation. The loss in correlated motions translates to not only a remarkable two orders of magnitude slower folding in the mutant but also to a proportionately complex unfolding mechanism. We thus propose that loss in correlated motions within cadherin-23 with aging may trigger ARHL, a molecular feature that likely holds true for other disease-mutations in \u03b2-strand-rich proteins.<\/jats:p>","DOI":"10.1042\/bcj20200799","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T14:31:40Z","timestamp":1607005900000},"page":"121-134","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Weakening of interaction networks with aging in tip-link protein induces hearing loss"],"prefix":"10.1042","volume":"478","author":[{"given":"Surbhi","family":"Garg","sequence":"first","affiliation":[{"name":"Department of Chemical Sciences, Indian Institute of Science Education and Research Mohali, Punjab, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amin","family":"Sagar","sequence":"additional","affiliation":[{"name":"Centre de Biochimie Structurale INSERM, CNRS, Universit\u00e9 de Montpellier, Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gayathri S.","family":"Singaraju","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences, Indian Institute of Science Education and Research Mohali, Punjab, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rahul","family":"Dani","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naimat K.","family":"Bari","sequence":"additional","affiliation":[{"name":"Institute of Nano Science and Technology (INST), Phase-10, Sector-64, Mohali, Punjab 160062, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1655-7802","authenticated-orcid":false,"given":"Athi N.","family":"Naganathan","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8083-6857","authenticated-orcid":false,"given":"Sabyasachi","family":"Rakshit","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences, Indian Institute of Science Education and Research Mohali, Punjab, India"},{"name":"Centre for Protein Science Design and Engineering, Indian Institute of Science Education and Research Mohali, Punjab, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2021,1,13]]},"reference":[{"key":"2021112218163027300_BCJ-2020-0799C1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/BF03324947","article-title":"Environmental and genetic factors in age-related hearing impairment","volume":"23","year":"2011","journal-title":"Aging Clin. 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