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Beta conformation of polyglutamine track revealed by a crystal structure of Huntingtin N-terminal region with insertion of three histidine residues.

Kim M
Prion 7 221-8
Related entries: 4fe8, 4feb, 4fec

Cited: 30 times
EuropePMC logo PMID: 23370273

Abstract

Huntington disease is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine (polyQ) expansion (> 35Q) in the first exon (EX1) of huntingtin protein (Htt). mHtt protein is thought to adopt one or more toxic conformation(s) that are involved in pathogenic interactions in cells . However, the structure of mHtt is not known. Here, we present a near atomic resolution structure of mHtt36Q-EX1. To facilitate crystallization, three histidine residues (3H) were introduced within the Htt36Q stretch resulting in the sequence of Q 7HQHQHQ 27. The Htt36Q3H region adopts α-helix, loop, β-hairpin conformations. Furthermore, we observed interactions between the backbone of the Htt36Q3H β-strand with the aromatic residues mimicking putative-toxic interactions with other proteins. Our findings support previous predictions that the expanded mHtt-polyQ region adopts a β-sheet structure. Detailed structural information about mHtt improves our understanding of the pathogenic mechanisms in HD and other polyQ expansion disorders and may form the basis for rational design of small molecules that target toxic conformations of disease-causing proteins.

Articles - 4fed mentioned but not cited (3)

  1. Beta conformation of polyglutamine track revealed by a crystal structure of Huntingtin N-terminal region with insertion of three histidine residues. Kim M. Prion 7 221-228 (2013)
  2. Critical assessment of coiled-coil predictions based on protein structure data. Simm D, Hatje K, Waack S, Kollmar M. Sci Rep 11 12439 (2021)
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Reviews citing this publication (7)

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Articles citing this publication (20)

  1. Regulation of Rvb1/Rvb2 by a Domain within the INO80 Chromatin Remodeling Complex Implicates the Yeast Rvbs as Protein Assembly Chaperones. Zhou CY, Stoddard CI, Johnston JB, Trnka MJ, Echeverria I, Palovcak E, Sali A, Burlingame AL, Cheng Y, Narlikar GJ. Cell Rep 19 2033-2044 (2017)
  2. HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19. He WT, Xue W, Gao YG, Hong JY, Yue HW, Jiang LL, Hu HY. Sci Rep 7 14797 (2017)
  3. Polyglutamine- and temperature-dependent conformational rigidity in mutant huntingtin revealed by immunoassays and circular dichroism spectroscopy. Fodale V, Kegulian NC, Verani M, Cariulo C, Azzollini L, Petricca L, Daldin M, Boggio R, Padova A, Kuhn R, Pacifici R, Macdonald D, Schoenfeld RC, Park H, Isas JM, Langen R, Weiss A, Caricasole A. PLoS One 9 e112262 (2014)
  4. Insights into the Aggregation Mechanism of PolyQ Proteins with Different Glutamine Repeat Lengths. Yushchenko T, Deuerling E, Hauser K. Biophys J 114 1847-1857 (2018)
  5. The folding equilibrium of huntingtin exon 1 monomer depends on its polyglutamine tract. Bravo-Arredondo JM, Kegulian NC, Schmidt T, Pandey NK, Situ AJ, Ulmer TS, Langen R. J Biol Chem 293 19613-19623 (2018)
  6. Emerging β-Sheet Rich Conformations in Supercompact Huntingtin Exon-1 Mutant Structures. Kang H, Vázquez FX, Zhang L, Das P, Toledo-Sherman L, Luan B, Levitt M, Zhou R. J Am Chem Soc 139 8820-8827 (2017)
  7. Assessment of transferable forcefields for protein simulations attests improved description of disordered states and secondary structure propensities, and hints at multi-protein systems as the next challenge for optimization. Abriata LA, Dal Peraro M. Comput Struct Biotechnol J 19 2626-2636 (2021)
  8. Conformational dynamics and self-association of intrinsically disordered Huntingtin exon 1 in cells. Büning S, Sharma A, Vachharajani S, Newcombe E, Ormsby A, Gao M, Gnutt D, Vöpel T, Hatters DM, Ebbinghaus S. Phys Chem Chem Phys 19 10738-10747 (2017)
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  10. Pathogenic polyglutamine expansion length correlates with polarity of the flanking sequences. Kim M. Mol Neurodegener 9 45 (2014)
  11. β-hairpin-mediated formation of structurally distinct multimers of neurotoxic prion peptides. Gill AC. PLoS One 9 e87354 (2014)
  12. Its preferential interactions with biopolymers account for diverse observed effects of trehalose. Hong J, Gierasch LM, Liu Z. Biophys J 109 144-153 (2015)
  13. AQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models. Hong H, Koon AC, Chen ZS, Wei Y, An Y, Li W, Lau MHY, Lau KF, Ngo JCK, Wong CH, Au-Yeung HY, Zimmerman SC, Chan HYE. J Biol Chem 294 2757-2770 (2019)
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  16. The Nature, Extent, and Consequences of Genetic Variation in the opa Repeats of Notch in Drosophila. Rice C, Beekman D, Liu L, Erives A. G3 (Bethesda) 5 2405-2419 (2015)
  17. Structure prediction of polyglutamine disease proteins: comparison of methods. Wen J, Scoles DR, Facelli JC. BMC Bioinformatics 15 Suppl 7 S11 (2014)
  18. Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington's disease. Zeng Y, Guo W, Xu G, Wang Q, Feng L, Long S, Liang F, Huang Y, Lu X, Li S, Zhou J, Burgunder JM, Pang J, Pei Z. Drug Des Devel Ther 10 1443-1451 (2016)
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