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Structural and mutational analysis of functional differentiation between synaptotagmins-1 and -7
Mingshan Xue1, Timothy K Craig, Ok-Ho Shin
1Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.
Plos One
|September 9, 2010
Summary
Functional differences in synaptotagmins, crucial for Ca2+-triggered exocytosis, stem from subtle sequence variations. Even minor changes in synaptotagmin-1 and synaptotagmin-7 C2B domains significantly impact their function.
Area of Science:
- Molecular Neuroscience
- Cell Biology
- Structural Biology
Background:
- Synaptotagmins are key regulators of Ca2+-triggered exocytosis, mediating diverse cellular functions via their C2 domains.
- Functional distinctions between synaptotagmin isoforms, such as synaptotagmin-1 and synaptotagmin-7, remain poorly understood, particularly regarding their roles as Ca2+ sensors in different cellular contexts.
Purpose of the Study:
- To investigate the molecular basis for the differential Ca2+ sensing functions of synaptotagmin-1 and synaptotagmin-7.
- To determine if structural differences in the C2B domain explain the distinct roles of synaptotagmin-1 and synaptotagmin-7 in Ca2+ signaling.
Main Methods:
- Performed rescue experiments in neurons from synaptotagmin-1 knockout mice using a synaptotagmin-1/synaptotagmin-7 chimera.
- Determined the crystal structure of the synaptotagmin-7 C2B domain at 1.44 Å resolution.
- Utilized NMR spectroscopy to analyze Ca2+-binding sites and compare with synaptotagmin-1.
Main Results:
- Rescue experiments using synaptotagmin-1/synaptotagmin-7 chimeras and mutants failed to restore function in synaptotagmin-1 knockout neurons.
- The crystal structure of the synaptotagmin-7 C2B domain revealed high similarity to synaptotagmin-1 C2B domain, with three Ca2+-binding sites.
- Two Ca2+-binding sites in synaptotagmin-7 C2B domain are analogous to those in synaptotagmin-1, suggesting crystal contacts may explain previous synaptotagmin-1 structural discrepancies.
Conclusions:
- Functional differentiation among synaptotagmin isoforms is driven by subtle sequence variations within their C2 domains.
- These minor sequence alterations lead to significant functional differences in Ca2+ sensing and exocytosis.
- The structural similarity of the C2B domains suggests that precise amino acid differences, rather than gross structural changes, dictate isoform-specific functions.
