Dephosphorylation accelerates the dissociation of ZAP70 from the T cell receptor

Author:

Goyette Jesse12ORCID,Depoil David3,Yang Zhengmin1ORCID,Isaacson Samuel A.4,Allard Jun5ORCID,van der Merwe P. Anton6ORCID,Gaus Katharina12,Dustin Michael L.3ORCID,Dushek Omer6ORCID

Affiliation:

1. European Molecular Biology Laboratory Australia Node in Single Molecule Science, School of Medical Sciences, University of New South Wales, Sydney 2052, NSW, Australia

2. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, Sydney 2052, NSW, Australia

3. The Kennedy Institute of Rheumatology, University of Oxford, OX3 7FY Oxford, United Kingdom

4. Department of Mathematics and Statistics, Boston University, Boston, MA 02215

5. Center for Complex Biological Systems, University of California, Irvine, CA 92697

6. Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom

Abstract

Significance Src homology 2 (SH2) domains are phosphotyrosine binding motifs that play key roles in cellular signaling. There are 110 proteins in the human genome containing SH2 binding domains, of which 10 contain tandem SH2 domains. Tandem domains have been shown to improve avidity and specificity and contribute to allostery. Here, we show that tandem SH2 domains can also exhibit binding lifetimes that are accelerated by the activity of phosphatases. This accelerated unbinding requires tandem SH2 domains to engage their substrates in dynamic binding modes that cycle between single SH2-bound states. We experimentally confirm that this is the case for the well-studied kinase ZAP70 binding the T cell receptor. We suggest that accelerated unbinding is a general feature of signaling networks.

Funder

Wellcome Trust

European Research Council

RCUK | Medical Research Council

Department of Health | National Health and Medical Research Council

National Science Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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