Issue 12, 2022

Synaptotagmin-1 C2B domains cooperatively stabilize the fusion stalk via a master-servant mechanism

Abstract

Synaptotagmin-1 is a low-affinity Ca2+ sensor that triggers synchronous vesicle fusion. It contains two similar C2 domains (C2A and C2B) that cooperate in membrane binding, being the C2B domain mainly responsible for the membrane fusion process due to its polybasic patch KRLKKKKTTIKK (321–332). In this work, a master-servant mechanism between two identical C2B domains is shown to control the formation of the fusion stalk in a calcium-independent manner. Two regions in C2B are essential for the process, the well-known polybasic patch and a recently described pair of arginines (398 399). The master domain shows strong PIP2 interactions with its polybasic patch and its pair of arginines. At the same time, the servant analogously cooperates with the master to reduce the total work to form the fusion stalk. The strategic mutation (T328E, T329E) in both master and servant domains disrupts the cooperative mechanism, drastically increasing the free energy needed to induce the fusion stalk, however, with negligible effects on the master domain interactions with PIP2. These data point to a difference in the behavior of the servant domain, which is unable to sustain its PIP2 interactions neither through its polybasic patch nor through its pair of arginines, and in the end, losing its ability to assist the master in the formation of the fusion stalk.

Graphical abstract: Synaptotagmin-1 C2B domains cooperatively stabilize the fusion stalk via a master-servant mechanism

Supplementary files

Article information

Article type
Edge Article
Submitted
01 12月 2021
Accepted
22 2月 2022
First published
23 2月 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 3437-3446

Synaptotagmin-1 C2B domains cooperatively stabilize the fusion stalk via a master-servant mechanism

A. L. Di Bartolo and D. Masone, Chem. Sci., 2022, 13, 3437 DOI: 10.1039/D1SC06711G

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