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A single structurally conserved SUMOylation site in CRMP2 controls NaV1.7 function
Erik Thomas Dustrude1, Samantha Perez-Miller1, Liberty François-Moutal1
1a Department of Pharmacology, College of Medicine , University of Arizona , Tucson , AZ , USA.
Channels (Austin, Tex.)
|March 10, 2017
Summary
Neuronal CRMP2 SUMOylation at lysine 374 regulates NaV1.7 channels. Phosphorylation-induced monomerization exposes this site, controlling channel activity.
Area of Science:
- Neuroscience
- Molecular Biology
- Structural Biology
Background:
- Neuronal Collapsin Response Mediator Protein 2 (CRMP2) is regulated by posttranslational modifications.
- CRMP2 SUMOylation (small ubiquitin-like modifier) is crucial for its interaction and trafficking of voltage-gated sodium channel NaV1.7.
Purpose of the Study:
- To identify biologically relevant SUMOylation sites on CRMP2.
- To investigate the functional consequence of CRMP2 SUMOylation on NaV1.7 channel activity.
Main Methods:
- Sequence alignment and structural analysis to predict SUMOylation sites.
- X-ray crystallography to determine the structure of mouse CRMP2 at 1.78 Å resolution.
- Electrophysiological recordings to measure NaV1.7 currents.
Main Results:
- Only lysine 374 was identified as a functional SUMOylation site on CRMP2.
- Loss of CRMP2 SUMOylation at lysine 374 reduced NaV1.7 currents.
- Crystal structure revealed lysine 374 is buried in the tetramer but exposed in the monomer.
Conclusions:
- CRMP2 SUMOylation at lysine 374 is a key regulatory mechanism for NaV1.7.
- Phosphorylation-dependent CRMP2 monomerization exposes lysine 374 for SUMOylation, leading to NaV1.7 regulation.
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