On the roles of intrinsically disordered proteins and regions in cell communication and signaling

Abstract

For proteins, the sequence → structure → function paradigm applies primarily to enzymes, transmembrane proteins, and signaling domains. This paradigm is not universal, but rather, in addition to structured proteins, intrinsically disordered proteins and regions (IDPs and IDRs) also carry out crucial biological functions. For these proteins, the sequence → IDP/IDR ensemble → function paradigm applies primarily to signaling and regulatory proteins and regions. Often, in order to carry out function, IDPs or IDRs cooperatively interact, either intra- or inter-molecularly, with structured proteins or other IDPs or intermolecularly with nucleic acids. In this IDP/IDR thematic collection published in Cell Communication and Signaling, thirteen articles are presented that describe IDP/IDR signaling molecules from a variety of organisms from humans to fruit flies and tardigrades (“water bears”) and that describe how these proteins and regions contribute to the function and regulation of cell signaling. Collectively, these papers exhibit the diverse roles of disorder in responding to a wide range of signals as to orchestrate an array of organismal processes. They also show that disorder contributes to signaling in a broad spectrum of species, ranging from micro-organisms to plants and animals.

Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing

“…The plot shows the biases in AA composition at N-terminal residues and explains the importance of sulfur-containing AAs and tryptophan at hydrophobic cores for protein rigidity. The absence of AAs, such as Cys and Trp, has been recognized by evolutionary studies about protein plasticity and disordered protein regions in previous studies ( Figure 2 ) [ 66 , 68 , 69 , 70 ].…”

“…Intrinsically disordered proteins (IDPs) execute various functions in all kinds of cellular processes [ 64 , 65 , 66 ]. The N-terminal regulatory domain of UNG2 possesses such an unstructured regional IDP motif (AA 1–92).…”

Conformational ensembles of intrinsically disordered proteins and flexible multidomain proteins

“…Based on disorder predictions, intrinsically disordered regions (IDRs) make up more than one third of eukaryotic proteins (Ward et al, 2004;Xue et al, 2012;Oates et al, 2013;Tunyasuvunakool et al, 2021). The conformational heterogeneity of IDPs allows for promiscuity in interaction partners, and IDPs are often involved in biological processes such as signaling, recognition, and regulation (Wright and Dyson, 2015;Bondos et al, 2021). In recent years, IDPs have received much attention for their role in the formation of a number of biomolecular condensates and membraneless organelles (Banani et al, 2017;Boeynaems et al, 2018;Peran and Mittag, 2020;Dignon et al, 2020;Choi et al, 2020;Martin and Holehouse, 2020;Borcherds et al, 2021).…”

Salt Induced Transitions in the Conformational Ensembles of Intrinsically Disordered Proteins

“…Salts have significant impact on the conformations sampled by intrinsically disordered proteins/regions (IDPs/IDRs). As a result, salts can affect diverse cellular functions of IDPs [1][2][3][4][5][6] such as cell signaling, 5,7 stress granule assembly, 8,9 heterochromatin formation, 10 transcription, etc. Furthermore, transitions in the conformational ensembles sampled by IDPs due to the changes in cellular environment can result in pathologies 9,11 such as neurodegenerative diseases 12 and cancer 13 through the formation of membraneless organelles 14 via liquid-liquid phase separation (LLPS).…”