The molecular language of membraneless organelles

Abstract

Eukaryotic cells organize their intracellular components into organelles that can be membrane-bound or membraneless. A large number of membraneless organelles, including nucleoli, Cajal bodies, P-bodies, and stress granules, exist as liquid droplets within the cell and arise from the condensation of cellular material in a process termed liquid-liquid phase separation (LLPS). Beyond a mere organizational tool, concentrating cellular components into membraneless organelles tunes biochemical reactions and improves cellular fitness during stress. In this review, we provide an overview of the molecular underpinnings of the formation and regulation of these membraneless organelles. This molecular understanding explains emergent properties of these membraneless organelles and shines new light on neurodegenerative diseases, which may originate from disturbances in LLPS and membraneless organelles.

Keywords: Cajal body; RNA binding protein; amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); chaperone; disaggregase; liquid–liquid phase separation; nucleolus; organelle; stress granule; subcellular organelle.

Figure 1.

LLPS phase separation in vitro and in vivo. A, in a mixture of two types of molecules, LLPS leads to the formation of two phases akin to droplets of oil appearing from a mixture of oil and water. Proteins can undergo a similar phase separation. In this case, the RBP FUS (olive circles) undergoes LLPS upon cleavage of the maltose-binding protein (MBP) tag (cyan circles) and forms liquid droplets that are enriched in FUS compared with the surrounding medium. B, LLPS underpins the biogenesis of a wide array of membraneless organelles within cells. Depicted here is a nonexhaustive list of these organelles.

Figure 2.

Critical interactions that drive LLPS. The interactions important in LLPS include cation–π, π–π, electrostatic, and transient cross–β-contacts. Proteins that undergo LLPS are enriched for low-complexity disordered regions and multivalent domains. Polymers of ions, such as RNA, may additionally act as scaffolds or molecular seeds for LLPS. The image for transient cross–β-contacts and LARKS comes from Hughes et al. (134).