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Synaptotagmin I's Intrinsically Disordered Region Interacts with Synaptic Vesicle Lipids and Exerts Allosteric

Michael E Fealey1,2, Ryan Mahling1, Anne M Rice1

  • 1Department of Chemistry and Biochemistry, University of Minnesota-Duluth , Duluth, Minnesota 55812, United States.

Biochemistry
|May 19, 2016
PubMed

Insights

Synaptotagmin I's disordered region modulates calcium binding and interacts with synaptic vesicle membranes. This intrinsically disordered region is sensitive to membrane lipids, suggesting a role in lipid-protein communication.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Synaptotagmin I (Syt I) is crucial for neurotransmitter release, sensing calcium influx.
  • The mechanism of allosteric signal propagation through Syt I's cytosolic domains is not fully understood.
  • The role of the intrinsically disordered region (IDR) in Syt I's calcium sensing and its interaction with membrane lipids remains unclear.

Purpose of the Study:

  • To investigate the role of Syt I's IDR in allosteric modulation of calcium (Ca2+) binding.
  • To determine the structural propensity of the IDR in response to varying membrane lipid compositions.
  • To elucidate the communication pathway between membrane lipids and Syt I's calcium-sensing domains.

Main Methods:

  • Differential scanning calorimetry (DSC) to assess thermal stability and binding.
  • Isothermal titration calorimetry (ITC) to quantify binding thermodynamics.
  • Nuclear magnetic resonance (NMR) spectroscopy to study protein-lipid interactions and structural dynamics.

Main Results:

  • The inclusion of the IDR was found to allosterically modulate Ca2+ binding to the first C2 domain (C2A).
  • NMR studies revealed that Syt I's IDR interacts with membranes mimicking synaptic vesicle lipid composition.
  • The IDR's interaction is highly sensitive to the specific lipid composition of the membrane.

Conclusions:

  • Syt I's IDR plays a significant role in regulating the protein's Ca2+ sensing capabilities.
  • The IDR is acutely sensitive to the surrounding membrane lipid environment.
  • The IDR serves as a critical interface for transmitting information about membrane lipid organization to the adjacent C2 domains.

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