Functional analysis of the interface between the tandem C2 domains of synaptotagmin-1

Molecular Biology of the Cell
Chantell S EvansEdwin R Chapman

Abstract

C2 domains are widespread motifs that often serve as Ca(2+)-binding modules; some proteins have more than one copy. An open issue is whether these domains, when duplicated within the same parent protein, interact with one another to regulate function. In the present study, we address the functional significance of interfacial residues between the tandem C2 domains of synaptotagmin (syt)-1, a Ca(2+) sensor for neuronal exocytosis. Substitution of four residues, YHRD, at the domain interface, disrupted the interaction between the tandem C2 domains, altered the intrinsic affinity of syt-1 for Ca(2+), and shifted the Ca(2+) dependency for binding to membranes and driving membrane fusion in vitro. When expressed in syt-1 knockout neurons, the YHRD mutant yielded reductions in synaptic transmission, as compared with the wild-type protein. These results indicate that physical interactions between the tandem C2 domains of syt-1 contribute to excitation-secretion coupling.

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Citations

Aug 1, 2018·Metallomics : Integrated Biometal Science·Sachin KattiTatyana I Igumenova
Aug 17, 2017·Nature·Qiangjun ZhouAxel T Brunger
Sep 11, 2019·Nature Communications·Nicholas A CourtneyEdwin R Chapman
Jun 5, 2019·Nature Communications·Kirill GrushinShyam S Krishnakumar
Mar 9, 2019·Frontiers in Plant Science·Jules D PetitEmmanuelle M Bayer
Jan 15, 2020·Nature Communications·Debasis DasEdwin R Chapman
Feb 15, 2017·Molecular Neurodegeneration·Katarzyna Marta ZoltowskaOksana Berezovska
Feb 23, 2020·Biophysical Journal·Sachin KattiTatyana I Igumenova
May 5, 2020·Neuron·Mazdak M BradberryEdwin R Chapman

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Methods Mentioned

BETA
atomic force microscopy
isothermal titration calorimetry
nuclear magnetic resonance
AFM
circular dichroism
NMR

Software Mentioned

ImageJ
MiniAnalysis
Igor
Nanoscope
Prism
FV10
JACoP
Clampfit
PATCHMASTER

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