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Plexina1 autoinhibition by the plexin sema domain
T Takahashi1, S M Strittmatter
1Department of Neurology and, Section of Neurobiology, Yale University School of Medicine, New Haven, CT 06510, USA
Neuron
|March 10, 2001
Summary
Semaphorin 3A (Sema3A) signaling uses PlexinA1 or PlexinA2 to guide axons. The sema domain of PlexinA1 autoinhibits the receptor, and Sema3A binding releases this inhibition.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Semaphorin 3A (Sema3A) is a key signaling molecule in axon guidance.
- Sema3A signals through a receptor complex involving neuropilin-1 (NP1) and Plexins.
- The precise mechanism of Plexin activation has remained incompletely understood.
Purpose of the Study:
- To elucidate the role of PlexinA1's sema domain in regulating its activation by Sema3A.
- To investigate the interaction between PlexinA1 ectodomain, NP1, and Sema3A.
- To determine which PlexinA family members can mediate Sema3A signaling.
Main Methods:
- Deletion analysis of the PlexinA1 ectodomain.
- Assessment of PlexinA1 activation through cellular responses (contraction, growth cone collapse, neurite outgrowth inhibition).
- Co-immunoprecipitation assays to study protein-protein interactions.
Main Results:
- Sema3A signals are transduced by PlexinA1 and PlexinA2, but not PlexinA3.
- The sema domain of PlexinA1 autoinhibits the receptor, preventing basal activation.
- Deletion of the sema domain results in constitutive PlexinA1 activation.
- The sema domain interacts with the rest of the PlexinA1 ectodomain and reverses constitutive activation.
- Both the sema domain and the remaining ectodomain of PlexinA1 associate with NP1 independently of Sema3A.
- Sema3A binding to the NP1/PlexinA1 complex releases the autoinhibition mediated by the sema domain.
Conclusions:
- PlexinA1 is autoinhibited by its sema domain.
- Sema3A binding to NP1 triggers a conformational change that releases PlexinA1 autoinhibition, leading to signal transduction.
- This study clarifies the mechanism of Plexin receptor activation in axon guidance signaling.
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