| Structural highlights
6x9o is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | HTT, HD, IT15 (HUMAN), F8A1, F8A2, F8A3 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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 PubMed
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 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 Also
References
- ↑ Pal A, Severin F, Lommer B, Shevchenko A, Zerial M. Huntingtin-HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington's disease. J Cell Biol. 2006 Feb 13;172(4):605-18. doi: 10.1083/jcb.200509091. PMID:16476778 doi:http://dx.doi.org/10.1083/jcb.200509091
- ↑ Huang ZN, Her LS. The Ubiquitin Receptor ADRM1 Modulates HAP40-Induced Proteasome Activity. Mol Neurobiol. 2017 Nov;54(9):7382-7400. doi: 10.1007/s12035-016-0247-y. Epub, 2016 Nov 5. PMID:27815841 doi:http://dx.doi.org/10.1007/s12035-016-0247-y
- ↑ Huang ZN, Chung HM, Fang SC, Her LS. Adhesion Regulating Molecule 1 Mediates HAP40 Overexpression-Induced Mitochondrial Defects. Int J Biol Sci. 2017 Nov 1;13(11):1420-1437. doi: 10.7150/ijbs.20742. eCollection, 2017. PMID:29209146 doi:http://dx.doi.org/10.7150/ijbs.20742
- ↑ Pal A, Severin F, Lommer B, Shevchenko A, Zerial M. Huntingtin-HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington's disease. J Cell Biol. 2006 Feb 13;172(4):605-18. doi: 10.1083/jcb.200509091. PMID:16476778 doi:http://dx.doi.org/10.1083/jcb.200509091
- ↑ 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. Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1. Commun Biol. 2021 Dec 8;4(1):1374. doi: 10.1038/s42003-021-02895-4. PMID:34880419 doi:http://dx.doi.org/10.1038/s42003-021-02895-4
|
