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  Exon Inclusion Modulates Conformational Plasticity and Autoinhibition of the Intersectin 1 SH3A Domain

Gerth, F., Jäpel, M., Sticht, J., Kuropka, B., Schmitt, X. J., Driller, J. H., et al. (2019). Exon Inclusion Modulates Conformational Plasticity and Autoinhibition of the Intersectin 1 SH3A Domain. Structure, 27(6), 977-987. doi:10.1016/j.str.2019.03.020.

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Item Permalink: https://hdl.handle.net/21.11116/0000-0003-BD7E-C Version Permalink: https://hdl.handle.net/21.11116/0000-0003-BE16-F
Genre: Journal Article

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 Creators:
Gerth, Fabian1, Author
Jäpel, Maria2, Author
Sticht, Jana1, 3, Author
Kuropka, Benno1, Author
Schmitt, Xiao Jakob4, 5, Author
Driller, Jan H.6, Author
Loll, Bernhard6, Author
Wahl, Markus C.6, Author
Pagel, Kevin4, Author
Haucke, Volker2, Author
Freund, Christian1, Author
Affiliations:
1Protein Biochemistry, Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany, ou_persistent22              
2Department of Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany, ou_persistent22              
3BioSupraMol Core Facility, Freie Universität Berlin, 14195 Berlin, Germany, ou_persistent22              
4Ion Mobility-Mass Spectrometry, Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany, ou_persistent22              
5Molecular Physics, Fritz Haber Institute, Max Planck Society, Berlin, DE, ou_634545              
6Structural Biochemistry, Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany, ou_persistent22              

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Free keywords: synapse SH3 domain alternative splicing autoinhibition NMR spectroscopy X-ray crystallography
 Abstract: 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 β 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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Language(s): eng - English
 Dates: 2018-08-172019-03-252019-04-252019-06-04
 Publication Status: Issued
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.str.2019.03.020
 Degree: -

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Title: Structure
  Other : Structure
Source Genre: Journal
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Publ. Info: London : Cell Press
Pages: - Volume / Issue: 27 (6) Sequence Number: - Start / End Page: 977 - 987 Identifier: ISSN: 0969-2126
CoNE: https://pure.mpg.de/cone/journals/resource/954927002244_1