{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T01:59:14Z","timestamp":1785376754807,"version":"3.55.0"},"reference-count":69,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The pathological expansion of the polyglutamine (polyQ) repeat within the first exon of huntingtin (Httex1) protein is a defining hallmark of Huntington's disease (HD). Multiple evidence supports that the membrane recruitment of Httex1 is critical for its self\u2010assembly and related toxicity in HD. In this work, we quantitatively examined the early steps of monomeric Httex1(23Q) association with lipid membranes and its impact on the conformational dynamics of the adjacent polyQ regions\u2014the N\u2010terminal N17 segment and C\u2010terminal proline\u2010rich region (PRR). A broad range of membrane physical properties was explored, including zwitterionic and anionic lipids, and also co\u2010existing liquid\u2010ordered and liquid\u2010disordered phases. Two single cysteine mutants were engineered at the N\u2010 and C\u2010termini of Httex1(23Q) and fluorescently labeled with acrylodan or Atto 488 to probe their local polarity and flexibility, respectively. Our results indicate that Httex1(23Q) preferentially binds to negatively charged lipid vesicles, and to a lower extent to liquid ordered\/disordered phases. The N\u2010terminal N17 segment interacts with anionic membranes, adopting a less flexible state than in aqueous solution. At variance, the C\u2010terminal PRR remains highly dynamic and solvent exposed in the Httex1(23Q) membrane\u2010bound state, preserving its intrinsic disordered features across all lipid compositions used. Altogether, our work provides quantitative insight into the distinct roles of each flanking polyQ region in mediating Httex1\u2010lipid binding, and how distinct lipid compositions further modulate these early interaction steps.<\/jats:p>","DOI":"10.1002\/pro.70612","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T10:56:24Z","timestamp":1778756184000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lipid composition controls the huntingtin exon 1 membrane\u2010association and differentially modulates its flanking regions' dynamics"],"prefix":"10.1002","volume":"35","author":[{"given":"T\u00e2nia","family":"Sousa","sequence":"first","affiliation":[{"name":"iBB\u2014Institute for Bioengineering and Biosciences Instituto Superior T\u00e9cnico, Universidade de Lisboa  Lisbon Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy at Instituto Superior 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