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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
*NOTE: In the version of this article initially published, the incorrect corresponding authors were listed. The corresponding author should be Pingwei Li (firstname.lastname@example.org). 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.
Ross, C.A. Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders. Neuron 35, 819–822 (2002).
Zoghbi, H.Y. & Orr, H.T. Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217–247 (2000).
Wanker, E.E. Protein aggregation and pathogenesis of Huntington's disease: mechanisms and correlations. Biol. Chem. 381, 937–942 (2000).
Masino, L. & Pastore, A. A structural approach to trinucleotide expansion diseases. Brain Res. Bull. 56, 183–189 (2001).
Perutz, M.F., Finch, J.T., Berriman, J. & Lesk, A. Amyloid fibers are water-filled nanotubes. Proc. Natl. Acad. Sci. USA 99, 5591–5595 (2002).
Perutz, M.F., Pope, B.J., Owen, D., Wanker, E.E. & Scherzinger, E. Aggregation of proteins with expanded glutamine and alanine repeats of the glutamine-rich and asparagine-rich domains of Sup35 and of the amyloid beta-peptide of amyloid plaques. Proc. Natl. Acad. Sci. USA 99, 5596–5600 (2002).
Thakur, A.K. & Wetzel, R. Mutational analysis of the structural organization of polyglutamine aggregates. Proc. Natl. Acad. Sci. USA 99, 17014–17019 (2002).
Thakur, A.K., Yang, W. & Wetzel, R. Inhibition of polyglutamine aggregate cytotoxicity by a structure-based elongation inhibitor. FASEB J. 18, 923–925 (2004).
Sikorski, P. & Atkins, E. New model for crystalline polyglutamine assemblies and their connection with amyloid fibrils. Biomacromolecules 6, 425–432 (2005).
Sharma, D., Shinchuk, L.M., Inouye, H., Wetzel, R. & Kirschner, D.A. Polyglutamine homopolymers having 8–45 residues form slablike beta-crystallite assemblies. Proteins 61, 398–411 (2005).
Baxa, U. et al. Filaments of the Ure2p prion protein have a cross-beta core structure. J. Struct. Biol. 150, 170–179 (2005).
Nelson, R. & Eisenberg, D. Recent atomic models of amyloid fibril structure. Curr. Opin. Struct. Biol. 16, 260–265 (2006).
Li, S.-H. et al. Interaction of Huntington disease protein with transcriptional activator Sp1. Mol. Cell. Biol. 22, 1277–1287 (2002).
Chen, S., Berthelier, V., Yang, W. & Wetzel, R. Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. J. Mol. Biol. 311, 173–182 (2001).
Lescure, A. et al. The N-terminal domain of the human TATA-binding protein plays a role in transcription from TATA-containing RNA polymerase II and III promoters. EMBO J. 13, 1166–1175 (1994).
Trottier, Y. et al. Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 378, 403–406 (1995).
Huang, C.C. et al. Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat. Cell Mol. Genet. 24, 217–233 (1998).
Persichetti, F. et al. Mutant huntingtin forms in vivo complexes with distinct context-dependent conformations of the polyglutamine segment. Neurobiol. Dis. 6, 364–375 (1999).
Foley, S., Curtis, J., Saudou, F. & Finkbeiner, S. Immunodominant pathological polyglutamine epitope. Soc. Neurosci. 26, 1294 (2000).
Peters-Libeu, C. et al. Crystallization and diffraction properties of the Fab fragment of 3B5H10, an antibody specific for disease-causing polyglutamine stretches. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. 61, 1065–1068 (2005).
Ko, J., Ou, S. & Patterson, P.H. New anti-huntingtin monoclonal antibodies: implications for huntingtin conformation and its binding proteins. Brain Res. Bull. 56, 319–329 (2001).
Trottier, Y. et al. Heterogeneous intracellular localization and expression of ataxin-3. Neurobiol. Dis. 5, 335–347 (1998).
Peters, M.F. & Ross, C.A. Isolation of a 40-kDa Huntingtin-associated protein. J. Biol. Chem. 276, 3188–3194 (2001).
Kazantsev, A. et al. A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila. Nat. Genet. 30, 367–376 (2002).
Tobin, A.J. & Signer, E.R. Huntington's disease: the challenge for cell biologists. Trends Cell Biol. 10, 531–536 (2000).
Masino, L., Kelly, G., Leonard, K., Trottier, Y. & Pastore, A. Solution structure of polyglutamine tracts in GST-polyglutamine fusion proteins. FEBS Lett. 513, 267–272 (2002).
Chen, S., Ferrone, F.A. & Wetzel, R. Huntington's disease age-of-onset linked to polyglutamine aggregation nucleation. Proc. Natl. Acad. Sci. USA 99, 11884–11889 (2002).
Bhattacharyya, A.M., Thakur, A.K. & Wetzel, R. Polyglutamine aggregation nucleation: thermodynamics of a highly unfavorable protein folding reaction. Proc. Natl. Acad. Sci. USA 102, 15400–15405 (2005).
Bennett, M.J. et al. A linear lattice model for polyglutamine in CAG-expansion diseases. Proc. Natl. Acad. Sci. USA 99, 11634–11639 (2002).
McGhee, J.D. & von Hippel, P.H. Theoretical aspects of DNA-protein interactions: co-operative and non-co-operative binding of large ligands to a one-dimensional homogeneous lattice. J. Mol. Biol. 86, 469–489 (1974).
Sambashivan, S., Liu, Y., Sawaya, M.R., Gingery, M. & Eisenberg, D. Amyloid-like fibrils of ribonuclease A with three-dimensional domain-swapped and native-like structure. Nature 437, 266–269 (2005).
Mangiarini, L. et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493–506 (1996).
Sanchez, P., Marche, P.N., Rueff-Juy, D. & Cazenave, P.A. Mouse V lambda x gene sequence generates no junctional diversity and is conserved in mammalian species. J. Immunol. 144, 2816–2820 (1990).
Adzhubei, A.A. & Sternberg, M.J.E. Left-handed polyproline II helices commonly occur in globular proteins. J. Mol. Biol. 229, 472–493 (1993).
Chellgren, B.W., Miller, A.-F. & Creamer, T.P. Evidence for polyproline II helical structure in short polyglutamine tracts. J. Mol. Biol. 361, 362–371 (2006).
Creamer, T.P. & Campbell, M.N. Determinants of the polyproline II helix from modeling studies. Adv. Protein Chem. 62, 263–282 (2002).
Wang, X., Vitalis, A., Wyczalkowski, M.A. & Pappu, R.V. Characterizing the conformational ensemble of monomeric polyglutamine. Proteins 63, 297–311 (2006).
Perisic, O., Webb, P.A., Holliger, P., Winter, G. & Williams, R.L. Crystal structure of a diabody, a bivalent antibody fragment. Structure 2, 1217–1226 (1994).
Katz, B.A. Binding of biotin to streptavidin stabilizes intersubunit salt bridges between Asp61 and His87 at low pH. J. Mol. Biol. 274, 776–800 (1997).
Khoshnan, A., Ko, J. & Patterson, P.H. Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. Proc. Natl. Acad. Sci. USA 99, 1002–1007 (2002).
Kelly, R.C., Jensen, D.E. & von Hipple, P.H. DNA “melting” proteins. IV. Fluorescence measurements of binding parameters for bacteriophage T4 gene 32-protein to mono-, oligo-, and polynucleotides. J. Biol. Chem. 251, 7240–7250 (1976).
Sundberg, E. & Mariuzza, R. Molecular recognition in antibody-antigen complexes. Adv. Protein Chem. 61, 119–160 (2002).
Dunah, A.W. et al. Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science 296, 2238–2243 (2002).
Heiser, V. et al. Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington's disease therapy. Proc. Natl. Acad. Sci. USA 97, 6739–6744 (2000).
Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760–763 (1994).
Brünger, A.T. et al. Crystallography & NMR System: a new software suite for macromolecular structure determination. Acta Crystallogr. D Biol. Crystallogr. 54, 905–921 (1998).
Lawrence, M.C. & Colman, P.M. Shape complementarity at protein/protein interfaces. J. Mol. Biol. 234, 946–950 (1993).
Altschuh, D., Vix, O., Rees, B. & Thierry, J.C. A conformation of cyclosporin A in aqueous environment revealed by the X-ray structure of a cyclosporin-Fab complex. Science 256, 92–94 (1992).
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).
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.).
The authors declare no competing financial interests.
MW1 sequence and comparison with other antibodies (PDF 99 kb)
Gel-filtration chromatography profiles (PDF 215 kb)
Structure comparisons (PDF 1213 kb)
Surface plasmon resonance binding data (PDF 218 kb)
MW1-polyQ interactions (PDF 84 kb)
About this article
Cite this article
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
Flanking Regions Determine the Structure of the Poly-Glutamine in Huntingtin through Mechanisms Common among Glutamine-Rich Human Proteins
Briefings in Bioinformatics (2020)
Scientific Reports (2019)
A General Strategy to Access Structural Information at Atomic Resolution in Polyglutamine Homorepeats
Angewandte Chemie International Edition (2018)
Biophysical Journal (2018)