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Incorporation ofglutamine repeatsmakes proteinoligomerize:implications forneurodegenerativediseases. Kelvin StottJonathan M. BlackburnP J Butler1995 год

Incorporation of glutamine repeats makes protein oligomerize: implications for neurodegenerative diseases.
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Аннотация: Many transcription factors and some other proteins contain glutamine repeats; their abnormal expansion has been linked to several dominantly inherited neuro-degenerative diseases. Having found that poly(L-glutamine) alone forms beta-strands held together by hydrogen bonds between their amide groups, we surmised that glutamine repeats may form polar zippers, an unusual motif for protein-protein interactions. To test this hypothesis, we have engineered a Gly-Gln10-Gly peptide into the inhibitory loop of truncated chymotrypsin inhibitor 2 (CI2), a small protein from barley seeds, by both insertion and replacement. Gel filtration resolved both mutant inhibitors into at least three fractions, which analytical ultracentrifugation identified as monomers, dimers, and trimers of the recombinant protein; the truncated wild-type CI2 formed only monomers. CD difference spectra of the dimers and trimers versus wild type indicated that their glutamine repeats formed beta-pleated sheets, while those of the monomers versus wild type were more suggestive of type I beta-turns. The CD spectra of all three fractions remained unchanged even after incubation at 70 degrees C; neither the dimers nor the trimers dissociated at this temperature. We argue that the stability of all three fractions is due to the multiplicity of hydrogen bonds between extended strands of glutamine repeats in the oligomers or within a beta-hairpin formed by the single glutamine repeat of each monomer. Pathological effects may arise when expanded glutamine repeats cause proteins to acquire excessively high affinities for each other or for other proteins with glutamine repeats.
Год издания: 1995
Авторы: Kelvin Stott, Jonathan M. Blackburn, P J Butler, M. F. Perutz
Издательство: National Academy of Sciences
Источник: Proceedings of the National Academy of Sciences
Ключевые слова: Genetic Neurodegenerative Diseases, Mitochondrial Function and Pathology, Ubiquitin and proteasome pathways
Другие ссылки: Proceedings of the National Academy of Sciences (HTML)
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Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
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