Functions of Intrinsically Disordered Regions

Abstract

Intrinsically disordered regions (IDRs), defined as protein segments lacking stable tertiary structures, are ubiquitously present in the human proteome and enriched with disease-associated mutations. IDRs harbor molecular recognition features (MoRFs) and post-translational modification sites (e.g., phosphorylation), enabling dynamic intermolecular interactions through conformational plasticity. Furthermore, IDRs drive liquid-liquid phase separation (LLPS) of biomacromolecules via multivalent interactions such as electrostatic attraction and pi-pi interactions, generating biomolecular condensates that are essential throughout the cellular lifecycle. These condensates separate intracellular space, forming a physical barrier to avoid interference between other molecules, thereby improving reaction specificity and efficiency. As a dynamically equilibrated process, LLPS formation and maintenance are regulated by multiple factors, endowing the condensates with rapid responsiveness to environmental cues and functional versatility in modulating diverse signaling cascades. Consequently, disruption of LLPS homeostasis can derail its associated biological processes, ultimately contributing to disease pathogenesis. Moreover, precisely because liquid-liquid phase separation (LLPS) is co-regulated by multiple factors, it may provide novel insights into the pathogenic mechanisms of disorders such as autism spectrum disorder (ASD), which result from the cumulative effects of multiple etiological factors.

Keywords: intrinsically disordered regions; liquid–liquid phase separation; molecular recognition features; post-translation modification.

Figure 1

Function of IDRs. (A) IDRs recognize molecules through conformational changes; (B) IDRs provide weak interaction forces for LLPS.

Figure 2

Factors causing liquid–liquid phase separation.

Figure 3

Dysregulation of phase-separation homeostasis leading to diseases.