Dipartimento di Chimica, Università degli Studi di Napoli Federico II, Via Cintia, I-80125 Napoli, Italy
Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, I-80134 Napoli, Italy
Centro Interuniversitario di Ricerca sui Peptidi Bioattivi (C.I.R.P.E.B.), Via Mezzocannone 16, I-80134 Napoli, Italy
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Meyer, E. F., Tollett Jr., W. J., WWWWhy does nature stutter? A survey of strands of repeated amino acids (2001) Acta Crystallogr D Biol Crystallogr, 57, pp. 181-18
Perutz, M. F., Glutamine repeats and neurodegenerative diseases: Molecular aspects (1999) Trends Biochem Sci, 24, pp. 58-63
Perutz, M. F., Windle, A. H., Cause of neural death in neurodegenerative diseases attributable to expansion of glutamine repeats (2001) Nature, 412, pp. 143-144
Margolis, R. L., Ross, C. A., Expansion explosion: New clues to the pathogenesis of repeat expansion neurodegenerative diseases (2001) Trends Mol Med, 7, pp. 479-482
Wanker, E. E., Protein aggregation and pathogenesis of Huntington's disease: Mechanisms and correlations (2000) Biol Chem, 381, pp. 937-942
Stine, O. C., Pleasant, N., Franz, M. L., Abbott, M. H., Folstein, S. E., Ross, C. A., Correlation between the onset age of Huntington's disease and length of the trinucleotide repeat in IT-15 (1993) Hum Mol Genet, 2, pp. 1547-1549
Ross, C. A., Poirier, M. A., Protein aggregation and neurodegenerative disease (2004) Nat Med, 10 (SUPPL.), pp. S10-S17
Davies, S. W., Turmaine, M., Cozens, B. A., Difiglia, M., Sharp, A. H., Ross, C. A., Scherzinger, E., Bates, G. P., Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation (1997) Cell, 90, pp. 537-548
Sisodia, S. S., Nuclear inclusions in glutamine repeat disorders: Are they pernicious, coincidental, or beneficial? (1998) Cell, 95, pp. 1-4
Temussi, P. A., Masino, L., Pastore, A., From Alzheimer to Huntington: Why is a structural understanding so difficult? (2003) EMBO J, 22, pp. 355-361
Perutz, M. F., Johnson, T., Suzuki, M., Finch, J. T., Glutamine repeats as polar zippers: Their possible role in inherited neurodegenerative diseases (1994) Proc Natl Acad Sci U S A, 91, pp. 5355-5358
Perutz, M. F., Finch, J. T., Berriman, J., Lesk, A., Amyloid fibers are water-filled nanotubes (2002) Proc Natl Acad Sci U S A, 99, pp. 5591-5595
Thakur, A. K., Wetzel, R., Mutational analysis of the structural organization of polyglutamine aggregates (2002) Proc Natl Acad Sci U S A, 99, pp. 17014-17019
Poirier, M. A., Jiang, H., Ross, C. A., A structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: Evidence for a compact beta-sheet structure (2005) Hum Mol Genet, 14, pp. 765-774
Polyglutamine Repeats And Beta-Helix Structure: Molecular Dynamics Study
Neurodegenerative diseases are often associated with the formation of highly insoluble aggregates. Despite the efforts devoted to the characterization of these aggregates, their structure remains elusive. Several neurodegenerative diseases are characterized by the expansion of CAG repeats, which code for Gln. Among the structural models proposed for the aggregates observed in polyQ-linked diseases, the nanotube beta-helix model proposed by Perutz and colleagues [Proc Natl Acad Sci USA 2002; 99: 5591-5595] has been influential. In the present study, the stability of this beta-helix model has been investigated by performing molecular dynamics simulations on polyQ fragments of different lengths. The results indicate that models shorter than two full beta-helix turns are unstable and collapse toward irregular structures. On the other hand, longer beta-helix models, containing more than 40 residues, achieve a dynamic regular structure. This finding is in line with the observed threshold of Gln repeats (approximate to 40) correlated with the insurgence of the disease. Notably, the structure of the final state of the models longer than 40 residues strictly depends on their size. A compact stable ellipsoidal structure is formed by the model made of two full helical turns (41 residues), whereas water filled tubular structures emerge from simulation on longer polypeptides. These results have been interpreted taking into account the experimental data on polyQ aggregates. A structural interpretation of the literature data has been proposed by assuming that different beta-helical models are involved in the different stages of the aggregation process. Proteins 2006; 63: 918-927. (c) 2006 Wiley-Liss, Inc
Polyglutamine Repeats And Beta-Helix Structure: Molecular Dynamics Study