Elucidating the molecular determinants of functional specificity in intrinsically disordered proteins

The National Institute of General Medical Sciences awarded the University of North Carolina at Chapel Hill $413,946 under the Biomedical Research and Research Training program (CFDA 93.859) on April 5, 2026, to support basic research elucidating the molecular determinants of functional specificity in intrinsically disordered proteins (IDPs).

The project investigates how IDPs achieve functional specificity through multivalent interactions—the linkage of multiple binding motifs within a single polypeptide chain. IDPs lack stable three-dimensional structures in isolation but are highly dynamic and context-dependent in binding, making them efficient regulators of cellular signaling and regulation. The research uses the fully disordered CITED family of transcriptional regulators as model systems to establish direct links between the physicochemical features of disordered proteins and specific biological functions. The work addresses a gap in understanding how highly flexible IDPs achieve specificity despite their conformational flexibility and environmental responsiveness.

Performance will occur in Chapel Hill, North Carolina, with an ultimate completion date of February 28, 2031. The award is classified as a Project Grant under NIGMS's assistance type structure. UNC-Chapel Hill is the prime recipient, operating through its Office of Sponsored Research. The University of North Carolina System Office serves as the parent organization.

Abstract

Intrinsically disordered proteins, or idps, have numerous essential roles in cellular signaling and regulation. In many ways, idps are ideally suited for carrying out important regulatory roles in complex environments. Idps do not adopt a single stable structure in isolation, are highly dynamic, and can engage multiple binding partners in a context-dependent manner. In addition, idps are highly responsive to the environment and can undergo changes in abundance, structure, dynamics, and interactions in response to chemical changes. This flexibility in form and function makes idps extremely efficient and adaptable regulators of biological processes. However, the precise physicochemical basis of these behaviors and the relationships between IDP conformational ensembles, sequence, dynamics, and function are poorly understood. Critically, even less is known about the mechanisms by which highly flexible idps achieve functional specificity through interactions with other cellular components. Growing evidence suggests that multivalency, or the linkage of multiple binding motifs in a single polypeptide chain, is a key feature that enables idps to carry out highly specific yet environmentally tunable functions in the cell. At present, the few systems for which the molecular features driving multivalent interactions have been well-described comprise a combination of disordered and folded domains, presenting a challenge for establishing a direct link between disorder and functional specificity achieved through multivalency. To address this GAP, we are studying the fully disordered cited family of transcriptional regulators as ideal model systems for dissecting the relationships between the molecular features of idps and specific biological functions. The cited proteins differ in size, sequence, and domain organization but all share a highly conserved c-terminal activation domain required for transcriptional regulation. The c-terminal activation domains of all cited proteins are implicated as molecular hubs for binding a multitude of cellular factors but the mechanistic basis of how these conserved segments selectively engage different molecular partners is not known. Further, the role of the variable n-termini and distinct compositional biases of the cited proteins in regulating the proteins' conformational ensembles, dynamics, and functions has yet to be elucidated. The overarching goals of this research program are: (1) to determine the mechanistic basis of molecular selectivity in protein-protein interactions involving idps, and (2) to understand the relationships between sequence compositional biases, environmental responsiveness, and functional specificity. As idps have a multitude of important roles in human health, the insights gained through this research will aid in establishing a new framework for considering functional specificity in the context of highly dynamic systems and will guide the design of new strategies for controlling the behavior of idps in a therapeutic context.