6x9o
From Proteopedia
High resolution cryoEM structure of huntingtin in complex with HAP40
Structural highlights
Disease[HD_HUMAN] Juvenile Huntington disease;Huntington disease. The disease is caused by mutations affecting the gene represented in this entry. [HAP40_HUMAN] Up-regulated in brain tissue from patients affected by Huntington's disease (at protein level) (PubMed:16476778). In a Huntington's disease mouse model overexpression of F8A1/F8A2/F8A3 impairs proteasome activity leading to the accumulation of mutant HTT and causes defective mitochondrial functions (PubMed:27815841, PubMed:29209146).[1] [2] [3] Function[HD_HUMAN] May play a role in microtubule-mediated transport or vesicle function. [HAP40_HUMAN] RAB5A effector molecule that is involved in vesicular trafficking of early endosomes (PubMed:16476778). Mediates the recruitment of HTT by RAB5A onto early endosomes. The HTT-F8A1/F8A2/F8A3-RAB5A complex stimulates early endosomal interaction with actin filaments and inhibits interaction with microtubules, leading to the reduction of endosome motility (PubMed:16476778).[4] Publication Abstract from PubMedHuntington'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 A 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. Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1.,Harding RJ, Deme JC, Hevler JF, Tamara S, Lemak A, Cantle JP, Szewczyk MM, Begeja N, Goss S, Zuo X, Loppnau P, Seitova A, Hutchinson A, Fan L, Truant R, Schapira M, Carroll JB, Heck AJR, Lea SM, Arrowsmith CH Commun Biol. 2021 Dec 8;4(1):1374. doi: 10.1038/s42003-021-02895-4. PMID:34880419[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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