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A linear lattice model for polyglutamine in CAG-expansion diseases

Bennett, Melanie J. and Huey-Tubman, Kathryn E. and Herr, Andrew B. and West, Anthony P., Jr. and Ross, Scott A. and Bjorkman, Pamela J. (2002) A linear lattice model for polyglutamine in CAG-expansion diseases. Proceedings of the National Academy of Sciences of the United States of America, 99 (18). pp. 11634-11639. ISSN 0027-8424. PMCID PMC129321. https://resolver.caltech.edu/CaltechAUTHORS:20141120-095244571

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Abstract

Huntington's disease and several other neurological diseases are caused by expanded polyglutamine [poly(Gln)] tracts in different proteins. Mechanisms for expanded (>36 Gln residues) poly(Gln) toxicity include the formation of aggregates that recruit and sequester essential cellular proteins [Preisinger, E., Jordan, B. M., Kazantsev, A. & Housman, D. (1999) Phil. Trans. R. Soc. London B 354, 1029–1034; Chen, S., Berthelier, V., Yang, W. & Wetzel, R. (2001) J. Mol. Biol. 311, 173–182] and functional alterations, such as improper interactions with other proteins [Cummings, C. J. & Zoghbi, H. Y. (2000) Hum. Mol. Genet. 9, 909–916]. Expansion above the “pathologic threshold” (≈36 Gln) has been proposed to induce a conformational transition in poly(Gln) tracts, which has been suggested as a target for therapeutic intervention. Here we show that structural analyses of soluble huntingtin exon 1 fusion proteins with 16 to 46 glutamine residues reveal extended structures with random coil characteristics and no evidence for a global conformational change above 36 glutamines. An antibody (MW1) Fab fragment, which recognizes full-length huntingtin in mouse brain sections, binds specifically to exon 1 constructs containing normal and expanded poly(Gln) tracts, with affinity and stoichiometry that increase with poly(Gln) length. These data support a “linear lattice” model for poly(Gln), in which expanded poly(Gln) tracts have an increased number of ligand-binding sites as compared with normal poly(Gln). The linear lattice model provides a rationale for pathogenicity of expanded poly(Gln) tracts and a structural framework for drug design.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.182393899DOIArticle
http://www.pnas.org/content/99/18/11634PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129321/PubMed CentralArticle
ORCID:
AuthorORCID
Huey-Tubman, Kathryn E.0000-0002-4683-8138
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2002 National Academy of Sciences. This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on May 1, 2001. Contributed by Pamela J. Bjorkman, July 3, 2002. We thank J. Ko and P. H. Patterson for providing MW1 hybridoma cell lines, Susan Ou in the Caltech Monoclonal Antibody Facility for ascites production, R. Myers and A. Kazantsev for proving HD exon 1 DNA templates, the California Institute of Technology Protein-Peptide MicroAnalytical Laboratory (PPMAL) for peptide and protein analyses, and A. M. Giannetti and W. L. Martin for assistance with data processing and helpful discussions. M.J.B. was supported by a fellowship from the Wills Foundation, K.E.H.-T. was supported by a grant from the Hereditary Disease Foundation Cure HD Initiative to M.J.B. and by the Howard Hughes Medical Institute, A.B.H. was supported by a fellowship from the Damon Runyon Cancer Research Foundation (DRG-1658), and A.P.W. was supported by a Burroughs Wellcome Fund Career Award in the Biomedical Sciences.
Funders:
Funding AgencyGrant Number
Wills FoundationUNSPECIFIED
Hereditary Disease FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Damon Runyon Cancer Research FoundationDRG-1658
Burroughs Wellcome FundUNSPECIFIED
Issue or Number:18
PubMed Central ID:PMC129321
Record Number:CaltechAUTHORS:20141120-095244571
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20141120-095244571
Official Citation:Bennett, M. J., Huey-Tubman, K. E., Herr, A. B., West, A. P., Ross, S. A., & Bjorkman, P. J. (2002). A linear lattice model for polyglutamine in CAG-expansion diseases. Proceedings of the National Academy of Sciences, 99(18), 11634-11639. doi: 10.1073/pnas.182393899
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:51993
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:20 Nov 2014 20:06
Last Modified:05 Nov 2019 21:32

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