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The structure of a polyQ–anti-polyQ complex reveals binding according to a linear lattice model

Li, Pingwei and Huey-Tubman, Kathryn E. and Gao, Tiyu and Li, Xiaojun and West, Anthony P., Jr. and Bennett, Melanie J. and Bjorkman, Pamela J. (2007) The structure of a polyQ–anti-polyQ complex reveals binding according to a linear lattice model. Nature Structural & Molecular Biology, 14 (5). pp. 381-387. ISSN 1545-9993. https://resolver.caltech.edu/CaltechAUTHORS:20150401-101018489

[img] PDF (Supplementary Fig. 1 MW1 sequence and comparison with other antibodies) - Supplemental Material
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[img] PDF (Supplementary Fig. 2 Gel-filtration chromatography profiles) - Supplemental Material
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[img] PDF (Figure 3Supplementary Fig. 3 Structure comparisons) - Supplemental Material
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[img] PDF (Supplementary Fig. 4 Surface plasmon resonance binding data) - Supplemental Material
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[img] PDF (Supplementary Table 1 MW1-polyQ interactions) - Supplemental Material
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[img] PDF (Supplementary Methods) - Supplemental Material
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Abstract

Huntington and related neurological diseases result from expansion of a polyglutamine (polyQ) tract. The linear lattice model for the structure and binding properties of polyQ proposes that both expanded and normal polyQ tracts in the preaggregation state are random-coil structures but that an expanded polyQ repeat contains a larger number of epitopes recognized by antibodies or other proteins. The crystal structure of polyQ bound to MW1, an antibody against polyQ, reveals that polyQ adopts an extended, coil-like structure. Consistent with the linear lattice model, multimeric MW1 Fvs bind more tightly to longer than to shorter polyQ tracts and, compared with monomeric Fv, bind expanded polyQ repeats with higher apparent affinities. These results suggest a mechanism for the toxicity of expanded polyQ and a strategy to link anti-polyQ compounds to create high-avidity therapeutics.


Item Type:Article
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http://dx.doi.org/10.1038/nsmb1234DOIArticle
http://www.nature.com/nsmb/journal/v14/n5/full/nsmb1234.html#closePublisherArticle
http://www.nature.com/nsmb/journal/v14/n5/suppinfo/nsmb1234_S1.htmlPublisherSupporting Information
http://rdcu.be/cr5pPublisherFree Readcube access
https://dx.doi.org/10.1038/nsmb0607-568aDOIErratum
ORCID:
AuthorORCID
Huey-Tubman, Kathryn E.0000-0002-4683-8138
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2007 Nature Publishing Group. Received 15 January; Accepted 14 March; Published online 22 April 2007; Corrected after print 8 May 2007. We thank A. Khoshnan and P.H. Patterson (California Institute of Technology) for the MW1 genes and hybridoma cell line, R. Wetzel (University of Tennessee Medical Center) for polyQ peptides, S. Sambashivan and D. Eisenberg (University of California, Los Angeles) for the RNase-10Q construct, D. King and A. Falick at the Howard Hughes Medical Institutes Mass Spectrometry Laboratory at University of California, Berkeley for the analysis of the MW1 Fab and A.B. Herr, A. Khoshnan, P.H. Patterson and members of the Bjorkman laboratory for comments on the manuscript. This work was supported by grants from the Huntington’s Disease Society of America and the Howard Hughes Medical Institute (P.J.B.) and by start-up funds from Texas A&M University (P.L.).
Errata:Erratum: The structure of a polyQ–anti-polyQ complex reveals binding according to a linear lattice model Pingwei Li, Kathryn E Huey-Tubman, Tiyu Gao, Xiaojun Li, Anthony P West, Jr, Melanie J Bennett & Pamela J Bjorkman Nature Structural & Molecular Biology 14, 568 (2007) doi:10.1038/nsmb0607-568a
Funders:
Funding AgencyGrant Number
Huntington’s Disease Society of AmericaUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Texas A&M UniversityUNSPECIFIED
Issue or Number:5
Record Number:CaltechAUTHORS:20150401-101018489
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150401-101018489
Official Citation:Li, P., Huey-Tubman, K. E., Gao, T., Li, X., West, A. P., Bennett, M. J., & Bjorkman, P. J. (2007). The structure of a polyQ-anti-polyQ complex reveals binding according to a linear lattice model. [10.1038/nsmb1234]. Nat Struct Mol Biol, 14(5), 381-387.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:56277
Collection:CaltechAUTHORS
Deposited By: Joanne McCole
Deposited On:01 Apr 2015 19:22
Last Modified:05 Nov 2019 21:36

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