Glutamine Repeats as Polar Zippers: Their Possible Role in Inherited Neurodegenerative Diseases

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 12; pp. 5355 - 5358
• Main Authors: Perutz, Max F., Johnson, Tony, Suzuki, Masashi, Finch, John T.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 07-06-1994; National Acad Sciences; National Academy of Sciences
• Subjects: Amides; Amino Acid Sequence; Biochemistry; conformation; Deoxyribonucleic acid; DNA; Genes; Genes, Dominant; Genetic inheritance; glutamine; Glutamine - chemistry; Humans; Huntingtin Protein; Huntington disease; Huntington Disease - etiology; Hydrogen Bonding; Hydrogen bonds; man; Molecular Sequence Data; Molecules; Muscular Atrophy, Spinal - etiology; Nerve Tissue Proteins - chemistry; Nervous system diseases; Neurodegenerative diseases; Neurological disorders; Nuclear Proteins - chemistry; Protein Binding; Protein Structure, Secondary; Proteins; Receptors, Androgen - chemistry; Repetitive Sequences, Nucleic Acid; Spinocerebellar Degenerations - etiology; X ray diffraction
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.12.5355

Four inherited neurodegenerative diseases are linked to abnormally expanded repeats of glutamine residues in the affected proteins. Molecular modeling followed by optical, electron, and x-ray diffraction studies of a synthetic poly(L-glutamine) shows that it forms β-sheets strongly held together by hydrogen bonds. Glutamine repeats may function as polar zippers, for example, by joining specific transcription factors bound to separate DNA segments. Their extension may cause disease either by increased, nonspecific affinity between such factors or by gradual precipitation of the affected proteins in neurons.