Decoding the selectivity of intrinsically disordered region interactions
A substantial portion of the protein kingdom consists of intrinsically disordered regions (IDRs) that do not fold into well-defined 3D structures yet perform numerous biological functions and are associated with a broad range of diseases. It has been a long-standing enigma how different IDRs successfully execute their specific functions. Further putting a spotlight on IDRs are recent discoveries of functionally relevant biomolecular assemblies, which in many cases form through liquid-liquid phase separation. At the molecular level, the formation of these biomolecular assemblies is largely driven by weak, multivalent, but selective IDR-IDR interactions, which are distinct from the folding-upon-binding process that a number of IDRs are known to undergo while forming complexes with fixed stoichiometries. Deciphering the multivalent interaction behaviors of IDRs in the context of biomolecular assembly formation, especially their selectivity of interaction partners, is key to understanding IDR functions. Emerging experimental and computational studies have indicated that amino acid sequence-derived features of IDRs may encode molecular recognition between different IDRs. However, the currently available information remains insufficient to build a comprehensive sequence-interaction-function paradigm for IDRs. It remains unclear how the interaction selectivity of an IDR is encoded in its sequence and how that selectivity affects the cellular functions of IDRs.
Figure adapted from Chong et al. (2021), J. Mol. Biol. 433, 166724
We probe the IDR sequence-function relationships using a combination of quantitative live-cell imaging, phase separation manipulation, proteomic, and bioinformatic approaches. We build novel experimental tools to characterize the multivalent interaction selectivity of diverse IDRs, identify sequence-derived features that determine the selectivity, and understand the functional consequences of the selective interactions. We begin by investigating transcription protein IDRs. The tools we develop are broadly applicable to phase-separation-prone IDRs involved in cellular processes beyond transcription. We aim to (1) elucidate how IDR-mediated biomolecular assemblies organize protein interactions to regulate diverse cellular functions in physiological and disease contexts and (2) enable the development of models that predict an IDR’s interaction partners and functions from its amino acid sequence.