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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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

Accession codes

Primary accessions

Protein Data Bank

Change history

  • 08 May 2007

    reference added and extra author corr address deleted


  1. 1.

    *NOTE: In the version of this article initially published, the incorrect corresponding authors were listed. The corresponding author should be Pingwei Li ( 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.


  1. 1

    Ross, C.A. Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders. Neuron 35, 819–822 (2002).

    CAS  Article  Google Scholar 

  2. 2

    Zoghbi, H.Y. & Orr, H.T. Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217–247 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Wanker, E.E. Protein aggregation and pathogenesis of Huntington's disease: mechanisms and correlations. Biol. Chem. 381, 937–942 (2000).

    CAS  Article  Google Scholar 

  4. 4

    Masino, L. & Pastore, A. A structural approach to trinucleotide expansion diseases. Brain Res. Bull. 56, 183–189 (2001).

    CAS  Article  Google Scholar 

  5. 5

    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).

    CAS  Article  Google Scholar 

  6. 6

    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).

    CAS  Article  Google Scholar 

  7. 7

    Thakur, A.K. & Wetzel, R. Mutational analysis of the structural organization of polyglutamine aggregates. Proc. Natl. Acad. Sci. USA 99, 17014–17019 (2002).

    CAS  Article  Google Scholar 

  8. 8

    Thakur, A.K., Yang, W. & Wetzel, R. Inhibition of polyglutamine aggregate cytotoxicity by a structure-based elongation inhibitor. FASEB J. 18, 923–925 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Sikorski, P. & Atkins, E. New model for crystalline polyglutamine assemblies and their connection with amyloid fibrils. Biomacromolecules 6, 425–432 (2005).

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  Article  Google Scholar 

  11. 11

    Baxa, U. et al. Filaments of the Ure2p prion protein have a cross-beta core structure. J. Struct. Biol. 150, 170–179 (2005).

    CAS  Article  Google Scholar 

  12. 12

    Nelson, R. & Eisenberg, D. Recent atomic models of amyloid fibril structure. Curr. Opin. Struct. Biol. 16, 260–265 (2006).

    CAS  Article  Google Scholar 

  13. 13

    Li, S.-H. et al. Interaction of Huntington disease protein with transcriptional activator Sp1. Mol. Cell. Biol. 22, 1277–1287 (2002).

    CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    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).

    CAS  Article  Google Scholar 

  16. 16

    Trottier, Y. et al. Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 378, 403–406 (1995).

    CAS  Article  Google Scholar 

  17. 17

    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).

    CAS  Article  Google Scholar 

  18. 18

    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).

    CAS  Article  Google Scholar 

  19. 19

    Foley, S., Curtis, J., Saudou, F. & Finkbeiner, S. Immunodominant pathological polyglutamine epitope. Soc. Neurosci. 26, 1294 (2000).

    Google Scholar 

  20. 20

    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).

    CAS  Article  Google Scholar 

  21. 21

    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).

    CAS  Article  Google Scholar 

  22. 22

    Trottier, Y. et al. Heterogeneous intracellular localization and expression of ataxin-3. Neurobiol. Dis. 5, 335–347 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Peters, M.F. & Ross, C.A. Isolation of a 40-kDa Huntingtin-associated protein. J. Biol. Chem. 276, 3188–3194 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Kazantsev, A. et al. A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila. Nat. Genet. 30, 367–376 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Tobin, A.J. & Signer, E.R. Huntington's disease: the challenge for cell biologists. Trends Cell Biol. 10, 531–536 (2000).

    CAS  Article  Google Scholar 

  26. 26

    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).

    CAS  Article  Google Scholar 

  27. 27

    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).

    CAS  Article  Google Scholar 

  28. 28

    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).

    CAS  Article  Google Scholar 

  29. 29

    Bennett, M.J. et al. A linear lattice model for polyglutamine in CAG-expansion diseases. Proc. Natl. Acad. Sci. USA 99, 11634–11639 (2002).

    CAS  Article  Google Scholar 

  30. 30

    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).

    CAS  Article  Google Scholar 

  31. 31

    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).

    CAS  Article  Google Scholar 

  32. 32

    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).

    CAS  Article  Google Scholar 

  33. 33

    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).

    CAS  PubMed  Google Scholar 

  34. 34

    Adzhubei, A.A. & Sternberg, M.J.E. Left-handed polyproline II helices commonly occur in globular proteins. J. Mol. Biol. 229, 472–493 (1993).

    CAS  Article  Google Scholar 

  35. 35

    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).

    CAS  Article  Google Scholar 

  36. 36

    Creamer, T.P. & Campbell, M.N. Determinants of the polyproline II helix from modeling studies. Adv. Protein Chem. 62, 263–282 (2002).

    CAS  Article  Google Scholar 

  37. 37

    Wang, X., Vitalis, A., Wyczalkowski, M.A. & Pappu, R.V. Characterizing the conformational ensemble of monomeric polyglutamine. Proteins 63, 297–311 (2006).

    CAS  Article  Google Scholar 

  38. 38

    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).

    CAS  Article  Google Scholar 

  39. 39

    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).

    CAS  Article  Google Scholar 

  40. 40

    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).

    CAS  Article  Google Scholar 

  41. 41

    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).

    CAS  PubMed  Google Scholar 

  42. 42

    Sundberg, E. & Mariuzza, R. Molecular recognition in antibody-antigen complexes. Adv. Protein Chem. 61, 119–160 (2002).

    Article  Google Scholar 

  43. 43

    Dunah, A.W. et al. Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science 296, 2238–2243 (2002).

    CAS  Article  Google Scholar 

  44. 44

    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).

    CAS  Article  Google Scholar 

  45. 45

    Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760–763 (1994).

  46. 46

    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).

    Article  Google Scholar 

  47. 47

    Lawrence, M.C. & Colman, P.M. Shape complementarity at protein/protein interfaces. J. Mol. Biol. 234, 946–950 (1993).

    CAS  Article  Google Scholar 

  48. 48

    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).

    CAS  Article  Google Scholar 

  49. 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).

    CAS  Article  Google Scholar 

Download references


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.).

Author information




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.

Corresponding author

Correspondence to Pingwei Li.

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and Permissions

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).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing