{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:33:18Z","timestamp":1791981198683,"version":"4.4.0"},"reference-count":41,"publisher":"American Chemical Society (ACS)","issue":"26","license":[{"start":{"date-parts":[[2015,8,6]],"date-time":"2015-08-06T00:00:00Z","timestamp":1438819200000},"content-version":"vor","delay-in-days":41,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_ccbyncnd_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000288","name":"Royal Society","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100000288","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000769","name":"University Of Oxford","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100000769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A gain-of-function mutation (T635A) in the transient receptor potential (TRP) channel TRPC3 results in abnormal channel gating and causes cerebellar ataxia in the dominant Moonwalker (Mwk) mouse mutant. However, the underlying molecular and structural mechanisms are unclear. Here, we used a combined approach of computational modeling and functional characterization of proposed TRPC3 mutants. Our findings support a mechanism by which the hydrogen bonding capability of threonine 635 plays a significant role in maintaining a stable, closed state channel. This capability is lost in the Mwk mutant, suggesting a structural basis for the disease-causing phenotype in the Mwk mouse.<\/jats:p>","DOI":"10.1021\/acs.biochem.5b00235","type":"journal-article","created":{"date-parts":[[2015,6,26]],"date-time":"2015-06-26T07:27:43Z","timestamp":1435303663000},"page":"4033-4041","source":"Crossref","is-referenced-by-count":16,"title":["Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation\nContributes to the Ataxia Phenotype of the\n                    <i>Moonwalker<\/i>\n                    Mouse"],"prefix":"10.1021","volume":"54","author":[{"given":"Sonya M.","family":"Hanson","sequence":"first","affiliation":[{"name":"National Institutes of Health , , , ,","place":["Bethesda, Maryland, United States, 20892"]},{"name":"University of Oxford , , South Parks Road , ,","place":["Oxford, United Kingdom, OX1 3QU"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark S. P.","family":"Sansom","sequence":"additional","affiliation":[{"name":"University of Oxford , , South Parks Road , ,","place":["Oxford, United Kingdom, OX1 3QU"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther B. E.","family":"Becker","sequence":"additional","affiliation":[{"name":"University of Oxford , , South Parks Road , ,","place":["Oxford, United Kingdom, OX1 3PT"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2015,6,26]]},"reference":[{"key":"2026090213185747500_cit1","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1146\/annurev.biochem.75.103004.142819","article-title":"TRP channels","volume":"76","author":"Venkatachalam","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"2026090213185747500_cit2","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1146\/annurev.physiol.68.040204.100431","article-title":"An introduction to TRP channels","volume":"68","author":"Ramsey","year":"2006","journal-title":"Annu. Rev. Physiol."},{"key":"2026090213185747500_cit3","doi-asserted-by":"crossref","first-page":"19689","DOI":"10.1523\/JNEUROSCI.2294-13.2013","article-title":"Early onset of ataxia\nin moonwalker mice is accompanied by complete ablation of type II\nunipolar brush cells and Purkinje cell dysfunction","volume":"33","author":"Sekerkova\u0301","year":"2013","journal-title":"J. Neurosci."},{"key":"2026090213185747500_cit4","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.neuron.2008.06.009","article-title":"TRPC3 channels are\nrequired for synaptic transmission and motor coordination","volume":"59","author":"Hartmann","year":"2008","journal-title":"Neuron"},{"key":"2026090213185747500_cit5","doi-asserted-by":"crossref","first-page":"6706","DOI":"10.1073\/pnas.0810599106","article-title":"A point\nmutation in TRPC3 causes abnormal Purkinje cell development and cerebellar\nataxia in moonwalker mice","volume":"106","author":"Becker","year":"2009","journal-title":"Proc. Natl. Acad.\nSci. U.S.A."},{"key":"2026090213185747500_cit6","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1007\/s12311-014-0564-5","article-title":"The\nmoonwalker mouse: New insights into TRPC3 function, cerebellar development,\nand ataxia","volume":"13","author":"Becker","year":"2014","journal-title":"Cerebellum"},{"key":"2026090213185747500_cit7","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/mds.26096","article-title":"Do mutations\nin the murine ataxia\ngene TRPC3 cause cerebellar ataxia in humans?","volume":"30","author":"Fogel","year":"2015","journal-title":"Mov. Disord."},{"key":"2026090213185747500_cit8","doi-asserted-by":"crossref","first-page":"19471","DOI":"10.1074\/jbc.M113.478305","article-title":"Conserved gating elements in TRPC4\nand TRPC5 channels","volume":"288","author":"Beck","year":"2013","journal-title":"J. Biol. Chem."},{"key":"2026090213185747500_cit9","doi-asserted-by":"crossref","first-page":"18321","DOI":"10.1073\/pnas.0709096104","article-title":"Activating\nmutation in a mucolipin transient receptor potential channel leads\nto melanocyte loss in varitint-waddler mice","volume":"104","author":"Xu","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090213185747500_cit10","doi-asserted-by":"crossref","first-page":"19607","DOI":"10.1073\/pnas.0708584104","article-title":"Yeast gain-of-function mutations\nreveal structure function relationships conserved among different\nsubfamilies of transient receptor potential channels","volume":"49","author":"Su","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090213185747500_cit11","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.ajhg.2012.02.006","article-title":"Exome sequencing reveals\nmutations in TRPV3 as a cause of Olmsted syndrome","volume":"90","author":"Lin","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"2026090213185747500_cit12","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1038\/ng.166","article-title":"Gain-of-function mutations in TRPV4\ncause autosomal dominant brachyolmia","volume":"40","author":"Rock","year":"2008","journal-title":"Nat. Genet."},{"key":"2026090213185747500_cit13","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nature12822","article-title":"Structure of the TRPV1 ion channel\ndetermined by electron cryo-microscopy","volume":"504","author":"Liao","year":"2013","journal-title":"Nature"},{"key":"2026090213185747500_cit14","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/nature12823","article-title":"TRPV1 structures in\ndistinct conformations reveal activation mechanisms","volume":"504","author":"Cao","year":"2013","journal-title":"Nature"},{"key":"2026090213185747500_cit15","doi-asserted-by":"crossref","first-page":"10251","DOI":"10.1523\/JNEUROSCI.22-23-10251.2002","article-title":"Number, density, and surface\/cytoplasmic\ndistribution of GABA transporters at presynaptic structures of knock-in\nmice carrying GABA transporter subtype 1\u2013green fluorescent\nprotein fusions","volume":"22","author":"Chiu","year":"2002","journal-title":"J. Neurosci."},{"key":"2026090213185747500_cit16","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1006\/jmbi.2000.4315","article-title":"Predicting\ntransmembrane protein topology with a hidden Markov model: Application\nto complete genomes","volume":"305","author":"Krogh","year":"2001","journal-title":"J. Mol. Biol."},{"key":"2026090213185747500_cit17","doi-asserted-by":"crossref","first-page":"3701","DOI":"10.1093\/nar\/gkg519","article-title":"GlobPlot:\nExploring protein sequences for globularity and disorder","volume":"31","author":"Linding","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"2026090213185747500_cit18","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1006\/jmbi.1999.3091","article-title":"Protein\nsecondary structure prediction based on position-specific scoring\nmatrices","volume":"292","author":"Jones","year":"1999","journal-title":"J. Mol. Biol."},{"key":"2026090213185747500_cit19","doi-asserted-by":"crossref","first-page":"W197","DOI":"10.1093\/nar\/gkn238","article-title":"The Jpred 3 secondary\nstructure prediction\nserver","volume":"36","author":"Cole","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"2026090213185747500_cit20","doi-asserted-by":"crossref","first-page":"8675","DOI":"10.1074\/jbc.273.15.8675","article-title":"The Membrane\nTopology of Human Transient\nReceptor Potential 3 as Inferred from Glycosylation-scanning Mutagenesis\nand Epitope Immunocytochemistry","volume":"273","author":"Vannier","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2026090213185747500_cit21","doi-asserted-by":"crossref","first-page":"3369","DOI":"10.1093\/bioinformatics\/bti534","article-title":"RONN: The bio-basis\nfunction neural network technique applied to the detection of natively\ndisordered regions in proteins","volume":"21","author":"Yang","year":"2005","journal-title":"Bioinformatics"},{"key":"2026090213185747500_cit22","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/j.str.2003.10.002","article-title":"Protein disorder\nprediction: Implications for structural\nproteomics","volume":"11","author":"Linding","year":"2003","journal-title":"Structure"},{"key":"2026090213185747500_cit23","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1093\/nar\/gkf436","article-title":"MAFFT: A novel\nmethod\nfor rapid multiple sequence alignment based on fast Fourier transform","volume":"30","author":"Katoh","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"2026090213185747500_cit24","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/S0076-6879(03)74020-8","article-title":"Modeller: Generation and refinement of homology-based protein structure\nmodels","volume":"374","author":"Fiser","year":"2003","journal-title":"Methods Enzymol."},{"key":"2026090213185747500_cit25","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/0079-6107(84)90007-5","article-title":"Hydrogen Bonding in Globular Proteins","volume":"44","author":"Baker","year":"1984","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"2026090213185747500_cit26","doi-asserted-by":"publisher","DOI":"10.1101\/008896","article-title":"MDTraj:\nA modern, open library for the analysis of molecular dynamics trajectories","author":"Mcgibbon","year":"2014","journal-title":"bioRxiv"},{"key":"2026090213185747500_cit27","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1107\/S0021889892009944","article-title":"PROCHECK: A program\nto check the stereochemical quality of protein structures","volume":"26","author":"Laskowski","year":"1993","journal-title":"J. Appl. Crystallogr."},{"key":"2026090213185747500_cit28","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1021\/ct100569y","article-title":"From Coarse Grained to Atomistic: A Serial Multiscale\nApproach to Membrane Protein Simulations","volume":"7","author":"Stansfeld","year":"2011","journal-title":"J.\nChem. Theory Comput."},{"key":"2026090213185747500_cit29","doi-asserted-by":"crossref","first-page":"7812","DOI":"10.1021\/jp071097f","article-title":"The MARTINI\nforce field: Coarse grained model for biomolecular simulations","volume":"111","author":"Marrink","year":"2007","journal-title":"J. Phys. Chem. B"},{"key":"2026090213185747500_cit30","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1021\/ct700301q","article-title":"GROMACS 4: Algorithms\nfor Highly Efficient, Load-Balanced, and Scalable Molecular Simulation","volume":"4","author":"Hess","year":"2008","journal-title":"J. Chem. Theory Comput."},{"key":"2026090213185747500_cit31","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1101\/gad.1102703","article-title":"Transcriptional regulation\nby calcium, calcineurin, and NFAT","volume":"17","author":"Hogan","year":"2003","journal-title":"Genes Dev."},{"key":"2026090213185747500_cit32","doi-asserted-by":"crossref","first-page":"4114","DOI":"10.1093\/hmg\/ddv150","article-title":"The\nmutant Moonwalker TRPC3 channel links calcium signaling\nto lipid metabolism in the developing cerebellum","volume":"24","author":"Dulneva","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2026090213185747500_cit33","doi-asserted-by":"crossref","first-page":"29031","DOI":"10.1074\/jbc.M302751200","article-title":"Regulation of canonical transient\nreceptor potential (TRPC) channel function by diacylglycerol and protein\nkinase C","volume":"278","author":"Venkatachalam","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2026090213185747500_cit34","doi-asserted-by":"crossref","first-page":"10556","DOI":"10.1073\/pnas.1106183108","article-title":"PKC-dependent\ncoupling of calcium permeation through\ntransient receptor potential canonical 3 (TRPC3) to calcineurin signaling\nin HL-1 myocytes","volume":"108","author":"Poteser","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090213185747500_cit35","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1124\/mol.104.007252","article-title":"Negative regulation\nof TRPC3 channels by protein kinase\nC-mediated phosphorylation of serine 712","volume":"67","author":"Trebak","year":"2005","journal-title":"Mol.\nPharmacol."},{"key":"2026090213185747500_cit36","doi-asserted-by":"crossref","first-page":"19854","DOI":"10.1074\/jbc.M801492200","article-title":"Enzymological\nanalysis of mutant protein kinase C\u03b3 causing\nspinocerebellar ataxia type 14 and dysfunction in Ca2+ homeostasis","volume":"283","author":"Adachi","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2026090213185747500_cit37","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1085\/jgp.200810048","article-title":"Kv channel gating requires a compatible\nS4-S5 linker and bottom part of S6, constrained by non-interacting\nresidues","volume":"132","author":"Labro","year":"2008","journal-title":"J. Gen. Physiol."},{"key":"2026090213185747500_cit38","doi-asserted-by":"crossref","first-page":"re15","DOI":"10.1126\/stke.2532004re15","article-title":"The VGL-chanome: A protein superfamily\nspecialized\nfor electrical signaling and ionic homeostasis","volume":"2004","author":"Yu","year":"2004","journal-title":"Sci. STKE"},{"key":"2026090213185747500_cit39","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nature14367","article-title":"Structure\nof the TRPA1 ion channel suggests regulatory mechanisms","volume":"520","author":"Paulsen","year":"2015","journal-title":"Nature"},{"key":"2026090213185747500_cit40","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1093\/bioinformatics\/btq554","article-title":"MEDELLER: Homology-based coordinate generation for\nmembrane proteins","volume":"26","author":"Kelm","year":"2010","journal-title":"Bioinformatics"},{"key":"2026090213185747500_cit41","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1002\/prot.20817","article-title":"Multipass membrane protein structure\nprediction using Rosetta","volume":"62","author":"Yarov-Yarovoy","year":"2006","journal-title":"Proteins"}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.biochem.5b00235","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/54\/26\/4033\/66940917\/acs.biochem.5b00235.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/54\/26\/4033\/66940917\/acs.biochem.5b00235.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:19:19Z","timestamp":1788369559000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/54\/26\/4033\/775401\/Modeling-Suggests-TRPC3-Hydrogen-Bonding-and-Not"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,6,26]]},"references-count":41,"journal-issue":{"issue":"26","published-online":{"date-parts":[[2015,6,26]]},"published-print":{"date-parts":[[2015,7,7]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.biochem.5b00235","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,6,26]]}}}