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The C\u2010terminal of the HTT protein consists mainly of HEAT repeat structure which serves as a scaffold for multiple cellular activities. Structural and biochemical analysis of the intact HTT protein has been hampered by its huge size (~300\u2009kDa) and most in vitro studies to date have focused on the properties of the exon 1 region. To explore the interaction between HTT exon 1 and the HEAT repeat structure, we constructed chimeric proteins containing the N\u2010terminal HTT exon 1 region and the HEAT repeat protein PR65\/A. The results indicate that HTT exon 1 slightly destabilizes the downstream HEAT repeat structure and endows the HEAT repeat structure with more conformational flexibility. Wild\u2010type and pathological lengths of polyQ did not show differences in the interaction between HTT exon 1 and the HEAT repeats. With the C\u2010terminal fusion of PR65\/A, HTT exon 1 containing pathological lengths of polyQ could still form amyloid fibrils, but the higher\u2010order architecture of fibrils and kinetics of fibril formation were affected by the C\u2010terminal fusion of HEAT repeats. This indicates that interaction between HTT exon 1 and HEAT repeat structure is compatible with both normal function of HTT protein and the pathogenesis of HD, and this study provides a potential model for further exploration.<\/jats:p>","DOI":"10.1002\/pro.4810","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T06:09:05Z","timestamp":1697695745000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Interaction between huntingtin exon 1 and <scp>HEAT<\/scp> repeat structure probed by chimeric model proteins"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9204-2547","authenticated-orcid":false,"given":"Hong","family":"Zhang","sequence":"first","affiliation":[{"name":"National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules Institute of Biophysics, Chinese Academy of Sciences  Beijing China"},{"name":"University 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