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

An Erratum to this article was published on 01 June 2007

This article has been updated

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.

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Figure 1: Crystal structures of the MW1 Fv alone and bound to GQ10G.
Figure 2: Peptide binding to MW1.

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  • 08 May 2007

    reference added and extra author corr address deleted

Notes

  1. 1.

    *NOTE: In the version of this article initially published, the incorrect corresponding authors were listed. The corresponding author should be Pingwei Li (pingwei@neo.tamu.edu). We apologize for this mistake.

    In addition, a paper was not cited. The missing citation is:

    49. Altschuler, E.L., Hud, N.V., Mazrimas, J.A. & Rupp, B. Random coil conformation for extended polyglutamine stretches in aqueous soluble monomeric peptides. J. Pept. Res. 50, 73–75 (1997).

    The citation should appear on page 381, in the eighth sentence of the article’s second paragraph, as follows: “However, studies involving polyQ peptides 14,26-28,49 , and our studies using polyQ tracts in the context of the HD exon 1 protein 29 , demonstrated that the predominant species of both normal and expanded unaggregated polyQ in solution is an extended random coil and showed no evidence for a detectable population of expanded soluble polyQ molecules with global conformational differences from normal polyQ.”

    These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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.).

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Authors

Contributions

P.L., M.J.B. and P.J.B. conceived the experiments. P.L. expressed the MW1 Fvs and solved the MW1 and MW1–GQ10G structures. K.E.H.-T. purified polyQ proteins, prepared MW1 Fabs and conducted crystallization trials for the MW1 Fab. T.G. and X.L. constructed and expressed SUMO-10Q and crystallized the MW1–GQ10G complex. P.L. and A.P.W. performed and analyzed the surface plasmon resonance experiments. P.L., M.J.B. and P.J.B. wrote the paper. All authors discussed and interpreted the results and commented on the manuscript.

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Correspondence to Pingwei Li.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

MW1 sequence and comparison with other antibodies (PDF 99 kb)

Supplementary Fig. 2

Gel-filtration chromatography profiles (PDF 215 kb)

Supplementary Fig. 3

Structure comparisons (PDF 1213 kb)

Supplementary Fig. 4

Surface plasmon resonance binding data (PDF 218 kb)

Supplementary Table 1

MW1-polyQ interactions (PDF 84 kb)

Supplementary Methods (PDF 183 kb)

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Li, P., Huey-Tubman, K., Gao, T. et al. The structure of a polyQ–anti-polyQ complex reveals binding according to a linear lattice model. Nat Struct Mol Biol 14, 381–387 (2007). https://doi.org/10.1038/nsmb1234

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