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  Isoform-selective interaction of the adaptor protein Tks5/FISH with Sos1 and dynamins

Rufer, A., Rumpf, J., von Holleben, M., Beer, S., Rittinger, K., & Groemping, Y. (2009). Isoform-selective interaction of the adaptor protein Tks5/FISH with Sos1 and dynamins. Journal of Molecular Biology (London), 390(5), 939-950. doi:10.1016/j.jmb.2009.05.025.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-126B-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-DED3-8
Genre: Journal Article

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 Creators:
Rufer, Arne1, Author              
Rumpf, Julia1, Author              
von Holleben, Max, Author
Beer, Sandra, Author
Rittinger, Katrin2, Author              
Groemping, Yvonne1, Author              
Affiliations:
1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              
2Emeritus Group Biophysics, Max Planck Institute for Medical Research, Max Planck Society, ou_1497712              

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Free keywords: protein-protein interaction; SH3 domain; specificity; isoform; signal transduction
 Abstract: The adaptor protein Tks5/FISH (tyrosine kinase substrate 5/five SH3 domains, hereafter termed Tks5) is a crucial component of a protein network that controls the invasiveness of cancer cells and progression of Alzheimer's disease. Tks5 consists of an amino-terminal PX domain that is followed by five SH3 domains (SH3A-E), and two different splice variants are expressed. We identified son of sevenless-1 (Sos1) as a novel binding partner of Tks5 and found colocalization of Tks5 with Sos1 in human epithelial lung carcinoma (A549) cells and in podosomes of Src-transformed NIH 3T3 cells. We observe synergistic binding of SH3A and SH3B to Sos1 when peptide arrays are used, indicating that the tandem SH3A and SH3B domains of Tks5 can potentially bind in a superSH3 binding mode, as was described for the homologous protein p47phox. These results are further corroborated by pull-down assays and isothermal titration calorimetry showing that both intact SH3 domains are required for efficient binding to the entire proline-rich domain of Sos1. The presence of a basic insertion between the SH3A and SH3B domains in the long splice variant of Tks5 decreases the affinity to Sos1 isoforms about 10-fold as determined by analytical ultracentrifugation. Furthermore, it leads to an alteration in the recognition of binding motifs for the interaction with Sos1: While the insertion abrogates the interaction with the majority of peptides derived from the proline-rich domains of Sos1 and dynamin that are recognized by the short splice isoform, it enables binding to a different set of peptides including a sequence comprising the splice insertion in the long isoform of Sos1 (Sos1_2). In the absence of the basic insertion, Tks5 was found to bind a range of Sos1 and dynamin peptides including conventional proline-rich motifs and atypical recognition sequences. Hereby, the tandem SH3 domains in Tks5 employ two distinct types of binding modes: One class of peptides is recognized by single SH3 domains, whereas a second class of peptides requires the presence of both domains to bind synergistically. We conclude that the tandem SH3A and SH3B domains of Tks5 constitute a versatile module for the implementation of isoform-specific protein-protein interactions.

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Language(s): eng - English
 Dates: 2009-05-122008-12-162009-05-142009-05-212009-07-31
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
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Title: Journal of Molecular Biology (London)
  Other : J Mol Biol
Source Genre: Journal
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Publ. Info: London : Academic Press
Pages: - Volume / Issue: 390 (5) Sequence Number: - Start / End Page: 939 - 950 Identifier: ISSN: 0022-2836
CoNE: /journals/resource/954922646042