Biomolecular Condensates: Sequence Determinants of Phase Separation, Microstructural Organization, Enzymatic Activity, and Material Properties

TLDR

Membraneless organelles form via phase separation, exhibiting diverse internal organization and tunable environments that can modulate enzymatic activity and material properties. The article aims to uncover sequence‑encoded rules governing condensate formation and to develop quantitative tools linking sequence, structure, and dynamics. It reviews diverse examples of condensate behavior and proposes improved quantitative characterization methods to elucidate sequence–structure–dynamics relationships.

Abstract

This perspective article highlights recent progress and emerging challenges in understanding the formation and function of membraneless organelles (MLOs). A long-term goal in the MLO field is to identify the sequence-encoded rules that dictate the formation of compositionally controlled biomolecular condensates, which cells utilize to perform a wide variety of functions. The molecular organization of the different components within a condensate can vary significantly, ranging from a homogeneous mixture to core–shell droplet structures. We provide many examples to highlight the richness of the observed behavior and potential research directions for improving our mechanistic understanding. The tunable environment within condensates can, in principle, alter enzymatic activity significantly. We examine recent examples where this was demonstrated, including applications in synthetic biology. An important question about MLOs is the role of liquid-like material properties in biological function. We discuss the need for improved quantitative characterization tools and the development of sequence–structure–dynamics relationships.