{"doi":"10.1038/s42003-021-02895-4","title":"Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1","abstract":"Huntington's disease results from expansion of a glutamine-coding CAG tract in the huntingtin (HTT) gene, producing an aberrantly functioning form of HTT. Both wildtype and disease-state HTT form a hetero-dimer with HAP40 of unknown functional relevance. We demonstrate in vivo and in cell models that HTT and HAP40 cellular abundance are coupled. Integrating data from a 2.6 Å cryo-electron microscopy structure, cross-linking mass spectrometry, small-angle X-ray scattering, and modeling, we provide a near-atomic-level view of HTT, its molecular interaction surfaces and compacted domain architecture, orchestrated by HAP40. Native mass spectrometry reveals a remarkably stable hetero-dimer, potentially explaining the cellular inter-dependence of HTT and HAP40. The exon 1 region of HTT is dynamic but shows greater conformational variety in the polyglutamine expanded mutant than wildtype exon 1. Our data provide a foundation for future functional and drug discovery studies targeting Huntington's disease and illuminate the structural consequences of HTT polyglutamine expansion.","journal":"Communications Biology","year":2021,"id":155425,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":59,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9457,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":634061,"name":"Justin C. Deme","orcid":"0000-0001-8811-9871","position":1,"is_corresponding":false},{"id":658095,"name":"Johannes F. Hevler","orcid":"0000-0001-6636-7145","position":2,"is_corresponding":false},{"id":658096,"name":"Sem Tamara","orcid":"0000-0002-6062-9404","position":3,"is_corresponding":false},{"id":375032,"name":"Alexander Lemak","orcid":null,"position":4,"is_corresponding":false},{"id":658097,"name":"Jeffrey P. Cantle","orcid":"0000-0001-6051-0465","position":5,"is_corresponding":false},{"id":277392,"name":"Magdalena M. Szewczyk","orcid":"0000-0001-9243-1630","position":6,"is_corresponding":false},{"id":658098,"name":"Nola Begeja","orcid":"0000-0002-9805-8037","position":7,"is_corresponding":false},{"id":658099,"name":"Siobhan Goss","orcid":"0000-0002-8518-7534","position":8,"is_corresponding":false},{"id":369909,"name":"Xiaobing Zuo","orcid":"0000-0002-0134-4804","position":9,"is_corresponding":false},{"id":36806,"name":"P. Loppnau","orcid":"0009-0004-0002-355X","position":10,"is_corresponding":false},{"id":659114,"name":"Alma Seitova","orcid":null,"position":11,"is_corresponding":false},{"id":36742,"name":"Ashley Hutchinson","orcid":"0000-0002-3481-8025","position":12,"is_corresponding":false},{"id":228421,"name":"Lixin Fan","orcid":"0000-0002-9232-9262","position":13,"is_corresponding":false},{"id":658100,"name":"Ray Truant","orcid":"0000-0003-2542-6641","position":14,"is_corresponding":false},{"id":36797,"name":"Matthieu Schapira","orcid":"0000-0002-1047-3309","position":15,"is_corresponding":false},{"id":260618,"name":"Jeffrey B. Carroll","orcid":"0000-0003-1711-8868","position":16,"is_corresponding":false},{"id":290017,"name":"Albert J. R. Heck","orcid":"0000-0002-2405-4404","position":17,"is_corresponding":false},{"id":634063,"name":"Susan M. Lea","orcid":"0000-0001-9287-8053","position":18,"is_corresponding":false},{"id":84362,"name":"C.H. Arrowsmith","orcid":"0000-0002-4971-3250","position":19,"is_corresponding":false},{"id":36735,"name":"Rachel J. Harding","orcid":"0000-0002-1134-391X","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-18T23:44:03.750995Z","pmid":"34880419","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}