| First Author | Emperador-Melero J | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 3057 |
| PubMed ID | 34031393 | Mgi Jnum | J:306331 |
| Mgi Id | MGI:6713949 | Doi | 10.1038/s41467-021-23116-w |
| Citation | Emperador-Melero J, et al. (2021) PKC-phosphorylation of Liprin-alpha3 triggers phase separation and controls presynaptic active zone structure. Nat Commun 12(1):3057 |
| abstractText | The active zone of a presynaptic nerve terminal defines sites for neurotransmitter release. Its protein machinery may be organized through liquid-liquid phase separation, a mechanism for the formation of membrane-less subcellular compartments. Here, we show that the active zone protein Liprin-alpha3 rapidly and reversibly undergoes phase separation in transfected HEK293T cells. Condensate formation is triggered by Liprin-alpha3 PKC-phosphorylation at serine-760, and RIM and Munc13 are co-recruited into membrane-attached condensates. Phospho-specific antibodies establish phosphorylation of Liprin-alpha3 serine-760 in transfected cells and mouse brain tissue. In primary hippocampal neurons of newly generated Liprin-alpha2/alpha3 double knockout mice, synaptic levels of RIM and Munc13 are reduced and the pool of releasable vesicles is decreased. Re-expression of Liprin-alpha3 restored these presynaptic defects, while mutating the Liprin-alpha3 phosphorylation site to abolish phase condensation prevented this rescue. Finally, PKC activation in these neurons acutely increased RIM, Munc13 and neurotransmitter release, which depended on the presence of phosphorylatable Liprin-alpha3. Our findings indicate that PKC-mediated phosphorylation of Liprin-alpha3 triggers its phase separation and modulates active zone structure and function. |
