How do disordered regions achieve comparable functions to structured domains?

Abstract

The traditional structure to function paradigm conceives of a protein's function as emerging from its structure. In recent years, it has been established that unstructured, intrinsically disordered regions (IDRs) in proteins are equally crucial elements for protein function, regulation and homeostasis. In this review, we provide a brief overview of how IDRs can perform similar functions to structured proteins, focusing especially on the formation of protein complexes and assemblies and the mediation of regulated conformational changes. In addition to highlighting instances of such functional equivalence, we explain how differences in the biological and physicochemical properties of IDRs allow them to expand the functional and regulatory repertoire of proteins. We also discuss studies that provide insights into how mutations within functional regions of IDRs can lead to human diseases.

Modulation of Intrinsically Disordered Protein Function by Post-translational Modifications

“…c-Src either resides in the cytoplasm or is attached to phospholipid membranes via a myristate group attached to the SH4 Gly 2 , a PTM necessary but not sufficient for membrane anchoring. The SH4 using residues 14 RRR 16 and the UD using the unique lipid binding region consisting of residues 60 -67 can each bind phospholipids directly. However, PKA phosphorylation of the SH4 Ser 17 and cyclin-dependent kinase phosphorylation of Ser 37 /Thr 75 of the UD disrupt such interactions (77).…”

“…This range of sequence composition leads to heterogeneous ensembles with variable hydrodynamic properties and fluctuating secondary and tertiary structure, with some IDPs able to self-associate in phaseseparated protein-dense droplets (6 -11). Structural heterogeneity and dynamic fluctuations endow IDPs with unique advantages over folded proteins for certain roles (12)(13)(14). IDPs expose, at least transiently, their entire primary sequence for binding, enabling multiple interactions along their polypeptide chains.…”

The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease

“…For instance, Q/N-rich regions are important for forming cellular assemblies, such as P-bodies, FG-rich regions are critical in forming the hydrogel-like structure of the nuclear pore, and repeats of multiple linear motifs can mediate phase separation and organize matter in cells, as seen in certain actin regulatory proteins (Figure 5) [92,99–102]. Thus, IDRs can mediate functions comparable to structured domains, such as (i) the formation of protein complexes and higher-order assemblies of variable stoichiometry of subunits [86], (ii) conformational transition (disorder-to-order and order-to-disorder) in response to specific environmental changes, context, or ligands [94], and (iii) allosteric communication [15,60,103–105]. Since most proteins contain structured and disordered regions in varying proportions, together with structured domains in the same polypeptide chain, IDRs can synergistically increase the functional versatility of proteins [12,15].…”

“…Thus, IDRs can mediate functions comparable to structured domains, such as (i) the formation of protein complexes and higher-order assemblies of variable stoichiometry of subunits [86], (ii) conformational transition (disorder-to-order and order-to-disorder) in response to specific environmental changes, context, or ligands [94], and (iii) allosteric communication [15,60,103–105]. Since most proteins contain structured and disordered regions in varying proportions, together with structured domains in the same polypeptide chain, IDRs can synergistically increase the functional versatility of proteins [12,15].

Figure 5.Formation of nonmembrane-bound organelles and higher-order assemblies by IDRs.( A ) Self-association.

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“…Instead, they adopt an ensemble of different conformations and can still carry out their function in an unstructured/disordered state [3–6]. These studies are now establishing the disorder–function paradigm (Figure 1B), which states that certain polypeptide segments can be functional without achieving a defined tertiary structure [7–15]. Recent studies that have investigated genome sequences of many organisms have established that over 40% of any eukaryotic proteome contains such disordered regions [16–18].…”