Differential Occurrence of Interactions and Interaction Domains in Proteins Containing Homopolymeric Amino Acid Repeats

Abstract

Homopolymeric amino acids repeats (AARs), which are widespread in proteomes, have often been viewed simply as spacers between protein domains, or even as “junk” sequences with no obvious function but with a potential to cause harm upon expansion as in genetic diseases associated with polyglutamine or polyalanine expansions, including Huntington disease and cleidocranial dysplasia. A growing body of evidence indicates however that at least some AARs can form organized, functional protein structures, and can regulate protein function. In particular, certain AARs can mediate protein-protein interactions, either through homotypic AAR-AAR contacts or through heterotypic contacts with other protein domains. It is still unclear however, whether AARs may have a generalized, proteome-wide role in shaping protein-protein interaction networks. Therefore, we have undertaken here a bioinformatics screening of the human proteome and interactome in search of quantitative evidence of such a role. We first identified the sets of proteins that contain repeats of any one of the 20 amino acids, as well as control sets of proteins chosen at random in the proteome. We then analyzed the connectivity between the proteins of the AAR-containing protein sets and we compared it with that observed in the corresponding control networks. We find evidence for different degrees of connectivity in the different AAR-containing protein networks. Indeed, networks of proteins containing polyglutamine, polyglutamate, polyproline, and other AARs show significantly increased levels of connectivity, whereas networks containing polyleucine and other hydrophobic repeats show lower degrees of connectivity. Furthermore, we observed that numerous protein-protein, -nucleic acid, and -lipid interaction domains are significantly enriched in specific AAR protein groups. These findings support the notion of a generalized, combinatorial role of AARs, together with conventional protein interaction domains, in shaping the interaction networks of the human proteome, and define proteome-wide knowledge that may guide the informed biological exploration of the role of AARs in protein interactions.

PolyQ-independent toxicity associated with novel translational products from CAG repeat expansions

“…This is consistent with previous findings that polyLeu peptides as short as nine repeats can spontaneously incorporate into lipid membranes [40,61,62]. Leucine occurs in many signal peptides and transmembrane domains [55]. For this reason, leucine is the most common amino acid in proteins that localize to the Endoplasmic Reticulum (ER), Golgi apparatus, or vacuoles [63].…”

Context characterization of amino acid homorepeats using evolution, position, and order

“…Domain enrichment analysis using PFAM annotations (see Material and Methods for details) indicates the over‐representation of specific domains in partners of human proteins with polyX. The interactors of proteins with polyP were enriched for SH3 domains ( P = 3.25e‐22), which are known to be the specific binders of polyproline helices . Intriguingly, we observed other similarly strong associations: RRM_1 domain associated with partners of polyA, polyG, polyS, and polyR proteins ( P = 5.49E‐24, 6.83E‐30, 3.30E‐23, and 1.29e‐8, respectively), and the Pkinase and Pkinase_Tyr domains with partners of polyK proteins ( P = 2.64E‐87 and 8.99E‐42, respectively).…”

Novel variants and clinical symptoms in four new ALG3‐CDG patients, review of the literature, and identification of AAGRP‐ALG3 as a novel ALG3 variant with alanine and glycine‐rich N‐terminus

“…For AAGRP‐ALG3 the considerable accumulation of alanine residues and alanine repeats in the N‐terminus is noteworthy because polyalanine stretches are known as a disease mechanism in congenital malformations, skeletal dysplasia, and nervous system anomalies (Amiel, Trochet, Clement‐Ziza, Munnich, & Lyonnet, ). The function of polyalanine repeats is still largely unclear, but they are thought to form coiled‐coil supersecondary structures which can then regulate the oligomerization, interactions and functions of proteins (Pelassa & Fiumara, ). Regrettably, our immunofluorescence studies concerning the localization of AAGRP‐ALG3 in mitochondria were inconclusive as polyalanine stretches were also found to induce mitochondrial dysfunction (Toriumi et al, ).…”