Evolution and function of CAG/polyglutamine repeats in protein–protein interaction networks

• Published in: Nucleic acids research Vol. 40; no. 10; pp. 4273 - 4287
• Main Authors: Schaefer, Martin H., Wanker, Erich E., Andrade-Navarro, Miguel A.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.05.2012
• Subjects: Amino Acid Sequence; Animals; Ataxia; Computational Biology; Computer programs; Evolution; Evolution, Molecular; Genome, Human; genomics; Humans; Information systems; Molecular Sequence Data; Multiprotein Complexes - chemistry; Peptides - genetics; Phylogeny; Polyglutamine; polyglutamine diseases; Protein interaction; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Proteins - chemistry; Proteins - genetics; Proteins - physiology; Sequence Alignment; trinucleotide repeat diseases; Trinucleotide Repeats
• DOI: 10.1093/nar/gks011
• ISSN: 0305-1048; 1362-4962

Expanded runs of consecutive trinucleotide CAG repeats encoding polyglutamine (polyQ) stretches are observed in the genes of a large number of patients with different genetic diseases such as Huntington's and several Ataxias. Protein aggregation, which is a key feature of most of these diseases, is thought to be triggered by these expanded polyQ sequences in disease-related proteins. However, polyQ tracts are a normal feature of many human proteins, suggesting that they have an important cellular function. To clarify the potential function of polyQ repeats in biological systems, we systematically analyzed available information stored in sequence and protein interaction databases. By integrating genomic, phylogenetic, protein interaction network and functional information, we obtained evidence that polyQ tracts in proteins stabilize protein interactions. This happens most likely through structural changes whereby the polyQ sequence extends a neighboring coiled-coil region to facilitate its interaction with a coiled-coil region in another protein. Alteration of this important biological function due to polyQ expansion results in gain of abnormal interactions, leading to pathological effects like protein aggregation. Our analyses suggest that research on polyQ proteins should shift focus from expanded polyQ proteins into the characterization of the influence of the wild-type polyQ on protein interactions.