Attributes of short linear motifs

Abstract

Traditionally, protein-protein interactions were thought to be mediated by large, structured domains. However, it has become clear that the interactome comprises a wide range of binding interfaces with varying degrees of flexibility, ranging from rigid globular domains to disordered regions that natively lack structure. Enrichment for disorder in highly connected hub proteins and its correlation with organism complexity hint at the functional importance of disordered regions. Nevertheless, they have not yet been extensively characterised. Shifting the attention from globular domains to disordered regions of the proteome might bring us closer to elucidating the dense and complex connectivity of the interactome. An important class of disordered interfaces are the compact mono-partite, short linear motifs (SLiMs, or eukaryotic linear motifs (ELMs)). They are evolutionarily plastic and interact with relatively low affinity due to the limited number of residues that make direct contact with the binding partner. These features confer to SLiMs the ability to evolve convergently and mediate transient interactions, which is imperative to network evolution and to maintain robust cell signalling, respectively. The ability to discriminate biologically relevant SLiMs by means of different attributes will improve our understanding of the complexity of the interactome and aid development of bioinformatics tools for motif discovery. In this paper, the curated instances currently available in the Eukaryotic Linear Motif (ELM) database are analysed to provide a clear overview of the defining attributes of SLiMs. These analyses suggest that functional SLiMs have higher levels of conservation than their surrounding residues, frequently evolve convergently, preferentially occur in disordered regions and often form a secondary structure when bound to their interaction partner. These results advocate searching for small groupings of residues in disordered regions with higher relative conservation and a propensity to form the secondary structure. Finally, the most interesting conclusions are examined in regard to their functional consequences.

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

“…80 These short functional linear motifs are hypothesized to have higher levels of conservation, to frequently evolve convergently, to preferentially occur in disordered regions and to often form a specific secondary structure when bound to interaction partners. 79 This observation fits in with the conception that alternative inclusion of exons in different tissues provides functional diversity of proteins. In fact, embedded conserved binding motifs and PTM sites are both rich in tissue-dependent protein segments.…”

“…As suggested by others, through parallel or convergent evolution, such MoRFs can exist as conserved functional motifs or regions among various species, such as human, mouse, yeast, E. coli, or even viruses. 79 As pointed out previously, 77 such short linear motifs are amenable to convergent evolution due to the limited number of mutations that are necessary for the generation of a useful motif. In fact, motifs are commonly used as adding new functional modules within a proteome, especially in higher eukaryotes.…”

A Proline-Tryptophan Turn in the Intrinsically Disordered Domain 2 of NS5A Protein Is Essential for Hepatitis C Virus RNA Replication

“…Whereas it is now well recognized that IDPs/IDRs are functional despite the lack of three-dimensional fold, the identification of the features that carry the function(s) remains challenging (34). Whether short linear motifs (35) or small residual structures (e.g. MoRFs, molecular recognition features (36); PreMos, pre-structured motifs (37)) that fold upon binding would carry the functions in IDRs is still under debate (34).…”

Evolution of domain–peptide interactions to coadapt specificity and affinity to functional diversity

“…As with most peptide binding domains, only few (approximately one-third) hot-spot residues in peptides are required for binding to SH3 domains (45,46). Basically, these residues identified as non-X sites (henceforth, "consensus residues") have specific amino acid identities, e.g., P and [RK] in [RK]XXPXXP and PXXPX [RK], and mutation of these residues disrupts binding, whereas wildcard positions identified as X sites (henceforth, "nonconsensus residues") can be mutated without altering binding (47).…”