Abstract
Fundamental discoveries have shaped our molecular understanding of presynaptic processes, such as neurotransmitter release, active zone organization and mechanisms of synaptic vesicle (SV) recycling. However, certain regulatory steps still remain incompletely understood. Protein liquid-liquid phase separation (LLPS) and its role in SV clustering and active zone regulation now introduce a new perception of how the presynapse and its different compartments are organized. This article highlights the newly emerging concept of LLPS at the synapse, providing a systematic overview on LLPS tendencies of over 500 presynaptic proteins, spotlighting individual proteins and discussing recent progress in the field. Newly discovered LLPS systems like ELKS/liprin-alpha and Eps15/FCho are put into context, and further LLPS candidate proteins, including epsin1, dynamin, synaptojanin, complexin and rabphilin-3A, are highlighted.
Highlights
When the first study demonstrated that proteins with low-complexity domains could undergo phase transition forming jelly-like hydrogels, this unveiled a new paradigm for the formation of subcellular compartments [1]
More and more membrane-less compartments are identified, and the understanding that the presynapse is sub-compartmentalized via liquid–liquid phase separation (LLPS) is emerging
This study identified 578 presynaptic proteins, for which the protein– protein interactions (PPIs) network showed six main protein hotspots
Summary
When the first study demonstrated that proteins with low-complexity domains could undergo phase transition forming jelly-like hydrogels, this unveiled a new paradigm for the formation of subcellular compartments [1]. More and more membrane-less compartments are identified, and the understanding that the presynapse is sub-compartmentalized via liquid–liquid phase separation (LLPS) is emerging. A protein’s tendency to undergo protein phase separation is conveyed by amino acid regions that do not adopt a well-defined structure and are called intrinsically disordered regions. These protein regions, until now, were more or less neglected for understanding a protein’s function because no clear role could be assigned. Protein regions with a less complex amino acid composition, called low-complexity domains, or protein regions with an enrichment of certain amino acids (i.e. proline, arginine, serine) tend to support weak protein– protein interactions (PPIs), known to be involved in LLPS
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