The diversity of molecular interactions involving intrinsically disordered proteins: A molecular modeling perspective

Abstract

Intrinsically Disordered Proteins and Regions (IDPs/IDRs) are key components of a multitude of biological processes. Conformational malleability enables IDPs/IDRs to perform very specialized functions that cannot be accomplished by globular proteins. The functional role for most of these proteins is related to the recognition of other biomolecules to regulate biological processes or as a part of signaling pathways. Depending on the extent of disorder, the number of interacting sites and the type of partner, very different architectures for the resulting assemblies are possible. More recently, molecular condensates with liquid-like properties composed of multiple copies of IDPs and nucleic acids have been proven to regulate key processes in eukaryotic cells. The structural and kinetic details of disordered biomolecular complexes are difficult to unveil experimentally due to their inherent conformational heterogeneity. Computational approaches, alone or in combination with experimental data, have emerged as unavoidable tools to understand the functional mechanisms of this elusive type of assemblies. The level of description used, all-atom or coarse-grained, strongly depends on the size of the molecular systems and on the timescale of the investigated mechanism. In this mini-review, we describe the most relevant architectures found for molecular interactions involving IDPs/IDRs and the computational strategies applied for their investigation.

The formation of a fuzzy complex in the negative arm regulates the robustness of the circadian clock

“…An understanding of how protein-protein interactions underly the mechanisms that regulate circadian feedback and post-transcriptional regulation has been hampered by the highly disordered nature of the core clock proteins. To investigate these proteinprotein interactions, we adapted an approach we termed LOCATE, which employs immobilized synthetic peptide microarrays to capture interactions across the full length of proteins enriched in IDRs (Clerc et al, 2021;Ivarsson and Jemth, 2019;Katz et al, 2011). Applying LOCATE to the N. crassa disordered negative-arm protein FRQ, we identified a SLiM hotspot beyond the genetically-identified binding region for FRH on FRQ, while also uncovering novel sites of FRH interaction.…”

APE1 assembles biomolecular condensates to promote the ATR-Chk1 DNA damage response in nucleolus

“…Importantly, NT33 motif of APE1 is indeed required for APE1 LLPS in vitro (Figure 4). LLPS is often driven by intrinsically disordered protein regions (IDRs) and/or association with nucleic acids such as RNA (86)(87)(88). Consistently, the NT33 motif is APE1's IDR whose structure has not been characterized yet, although other, more ridged, regions of APE1 have been fully characterized (89,90).…”

Short Linear Motifs in Colorectal Cancer Interactome and Tumorigenesis

“…SLiMs are the minimum sequence determinants that can finely modulate cellular PPI networks independently of the wider sequence/structure context where they function [ 11 ]. Frequently, SLiMs correspond to consensus sequence patterns located in the disordered regions of proteins, where they mediate transient and low-affinity interactions with various interactors due to their structural flexibility [ 17 , 18 ]. This makes them ideal to mediate dynamic processes such as cell signaling.…”