info:eu-repo/semantics/article
Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis
Fecha
2018-08Registro en:
Bello, Oscar Daniel; Jouannot, Ouardane; Chaudhuri, Arunima; Stroeva, Ekaterina; Coleman, Jeff; et al.; Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 115; 32; 8-2018; 7624-7631
0027-8424
CONICET Digital
CONICET
Autor
Bello, Oscar Daniel
Jouannot, Ouardane
Chaudhuri, Arunima
Stroeva, Ekaterina
Coleman, Jeff
Volynski, Kirill E.
Rothman, James E.
Krishnakumar, Shyam S.
Resumen
Regulated exocytosis, which underlies many intercellular signaling events, is a tightly controlled process often triggered by calcium ion(s) (Ca2+). Despite considerable insight into the central components involved, namely, the core fusion machinery [soluble N-ethylmaleimide?sensitive factor attachment protein receptor (SNARE)] and the principal Ca2+ sensor [C2-domain proteins like synaptotagmin (Syt)], the molecular mechanism of Ca2+-dependent release has been unclear. Here, we report that the Ca2+-sensitive oligomers of Syt1, a conserved structural feature among several C2-domain proteins, play a critical role in orchestrating Ca2+-coupled vesicular release. This follows from pHluorin-based imaging of single-vesicle exocytosis in pheochromocytoma (PC12) cells showing that selective disruption of Syt1 oligomerization using a structure-directed mutation (F349A) dramatically increases the normally low levels of constitutive exocytosis to effectively occlude Ca2+-stimulated release. We propose a parsimonious model whereby Ca2+-sensitive oligomers of Syt (or a similar C2-domain protein) assembled at the site of docking physically block spontaneous fusion until disrupted by Ca2+. Our data further suggest Ca2+-coupled vesicular release is triggered by removal of the inhibition, rather than by direct activation of the fusion machinery.