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

Abstract

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.

A Network of Interdependent Molecular Interactions Describes a Higher Order Nrd1-Nab3 Complex Involved in Yeast Transcription Termination

“…The polyglutamine regions appear to be structurally dynamic, having the ability to adopt many types of secondary structure, including extended conformations, ␣-helices, and ␤-sheets (31). The protein sequence adjacent to polyglutamine stretches also plays a role in conformation because polyglutamine tracts tend to be non-randomly distributed and frequently neighbor helical coiled coil elements (32)(33)(34). Some RNA-binding proteins with low complexity sequences form cytoplasmic foci, such as stress granules that harbor enzymes and substrates of RNA metabolism.…”

Dynamic Imaging by Fluorescence Correlation Spectroscopy Identifies Diverse Populations of Polyglutamine Oligomers Formed in Vivo

“…A plethora of proteins have been identified that interact with polyQ and affect its aggregation and toxicity (31)(32)(33). These proteins are involved in many cellular processes including protein folding and clearance, transcription, and cell structure.…”

Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

“…This view is supported by systematic computational and experimental investigations of polyQ-containing proteins, which suggest that polyQ domains mediate protein-protein interactions [1]. For example, polyQ sequences in transcription factors can influence gene expression in yeast and mammalian cells by promoting the formation of regulatory protein complexes that facilitate transcriptional activation [2][3][4].…”

“…Philipp Trepte, Nadine Strempel, Erich E. Wanker 1 Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Roessle-Str. 10,13125 Berlin, Germany…”

“…Polyglutamine (polyQ) tracts with lengths between 5 and 30 glutamines are conserved and found in 0.34% of all human proteins, indicating that they play an important functional role [1]. This view is supported by systematic computational and experimental investigations of polyQ-containing proteins, which suggest that polyQ domains mediate protein-protein interactions [1].…”