期刊
STRUCTURE
卷 27, 期 6, 页码 977-+出版社
CELL PRESS
DOI: 10.1016/j.str.2019.03.020
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资金
- Helmholz Zentrum Berlin fur Materialien und Energie
- Freie Universitat Berlin
- Humboldt-Universitat zu Berlin
- Max-Delbruck Centrum
- Leibniz-Forschungsinstitut fur Molekulare Pharmakologie
- German Research Foundation [SFB958/A07]
The scaffolding protein intersectin 1 plays important roles in clathrin-mediated endocytosis and in the replenishment of release-ready synaptic vesicles (SV). Two splice variants of intersectin's SH3A domain are expressed in the brain, and association of the neuron-specific variant with synapsin I has been shown to enable sustained neurotransmission and to be regulated by an adjacent C-terminal motif. Here, we demonstrate that the ubiquitously expressed short SH3A variant of intersectin 1 interacts with an N-terminal intramolecular sequence that operates synergistically with the C-terminal motif. NMR spectroscopic investigations show that the five-amino acid insertion into the beta strand 2 of the neuronal SH3A variant introduces conformational plasticity incompatible with binding of the N-terminal sequence. The difference in the autoregulatory mechanism of the domain's variants differentially affects its synaptic binding partners, thereby establishing alternative splicing in conjunction with autoinhibitory motif variation as a mechanism to regulate protein interaction networks.
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