6x9o
From Proteopedia
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==High resolution cryoEM structure of huntingtin in complex with HAP40== | ==High resolution cryoEM structure of huntingtin in complex with HAP40== | ||
| - | <StructureSection load='6x9o' size='340' side='right'caption='[[6x9o]]' scene=''> | + | <StructureSection load='6x9o' size='340' side='right'caption='[[6x9o]], [[Resolution|resolution]] 2.60Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6X9O OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6x9o]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6X9O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6X9O FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HTT, HD, IT15 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), F8A1, F8A2, F8A3 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6x9o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6x9o OCA], [https://pdbe.org/6x9o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6x9o RCSB], [https://www.ebi.ac.uk/pdbsum/6x9o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6x9o ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[https://www.uniprot.org/uniprot/HD_HUMAN HD_HUMAN]] Juvenile Huntington disease;Huntington disease. The disease is caused by mutations affecting the gene represented in this entry. [[https://www.uniprot.org/uniprot/HAP40_HUMAN 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).<ref>PMID:16476778</ref> <ref>PMID:27815841</ref> <ref>PMID:29209146</ref> | ||
| + | == Function == | ||
| + | [[https://www.uniprot.org/uniprot/HD_HUMAN HD_HUMAN]] May play a role in microtubule-mediated transport or vesicle function. [[https://www.uniprot.org/uniprot/HAP40_HUMAN 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).<ref>PMID:16476778</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:34880419</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6x9o" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Huntingtin|Huntingtin]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Arrowsmith | + | [[Category: Arrowsmith, C H]] |
| - | [[Category: Deme | + | [[Category: Deme, J C]] |
| - | [[Category: Harding | + | [[Category: Harding, R J]] |
| - | [[Category: Lea | + | [[Category: Lea, S M]] |
| + | [[Category: Structural genomic]] | ||
| + | [[Category: 40-kda huntingtin-associated protein]] | ||
| + | [[Category: Hap40]] | ||
| + | [[Category: Htt]] | ||
| + | [[Category: Huntingtin]] | ||
| + | [[Category: Protein binding]] | ||
| + | [[Category: Sgc]] | ||
Revision as of 11:10, 30 March 2022
High resolution cryoEM structure of huntingtin in complex with HAP40
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