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Synthesis of pathological and nonpathological human exon 1 huntingtin
Author(s) -
Singer David,
Zauner Thomas,
Genz Maika,
Hoffmann Ralf,
Zuchner Thole
Publication year - 2010
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.1252
Subject(s) - huntingtin , exon , polyproline helix , circular dichroism , peptide , huntingtin protein , glutamine , amino acid , peptide sequence , protein secondary structure , trinucleotide repeat expansion , chemistry , biochemistry , protein structure , microbiology and biotechnology , polyglutamine tract , biology , gene , mutant , allele
Huntington's disease (HD) is a neurodegenerative disorder that affects approximately 1 in 10 000 individuals. The underlying gene mutation was identified as a CAG‐triplet repeat expansion in the gene huntingtin . The CAG sequence codes for glutamine, and in HD, an expansion of the polyglutamine (poly‐Q) stretch above 35 glutamine residues results in pathogenicity. It has been demonstrated in various animal models that only the expression of exon 1 huntingtin, a 67‐amino acid‐long polypeptide plus a variable poly‐Q stretch, is sufficient to cause full HD‐like pathology. Therefore, a deeper understanding of exon 1 huntingtin, its structure, aggregation mechanism and interaction with other proteins is crucial for a better understanding of the disease. Here, we describe the synthesis of a 109‐amino acid‐long exon 1 huntingtin peptide including a poly‐Q stretch of 42 glutamines. This microwave‐assisted solid phase peptide synthesis resulted in milligram amounts of peptide with high purity. We also synthesized a nonpathogenic version of exon 1 huntingtin (90‐amino acid long including a poly‐Q stretch of 23 glutamine residues) using the same strategy. In circular dichroism spectroscopy, both polypeptides showed weak alpha‐helical properties with the longer peptide showing a higher helical degree. These model peptides have great potential for further biomedical analyses, e.g. for large‐scale pre‐screenings for aggregation inhibitors, further structural analyses as well as protein–protein interaction studies. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.