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Cited by 57Protein Kinase Regulation and GTPase SignalingCellular transport and secretionProtein Tyrosine Phosphatases

Rac regulates its effector phospholipase Cγ2 through interaction with a split pleckstrin homology domain

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Walliser, Claudia, Retlich, Michael, Harris, Richard, Everett, Katy L., Josephs, Michelle B., Vatter, Petra, Esposito, Diego, Driscoll, Paul C. +3 more·2008·Journal of Biological Chemistry
DOI 10.1074/jbc.m803316200PMC PMC2573054
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Abstract

Several isoforms of phospholipase C (PLC) are regulated through interactions with Ras superfamily GTPases, including Rac proteins. Interestingly, of two closely related PLCgamma isoforms, only PLCgamma(2) has previously been shown to be activated by Rac. Here, we explore the molecular basis of this interaction as well as the structural properties of PLCgamma(2) required for activation. Based on reconstitution experiments with isolated PLCgamma variants and Rac2, we show that an unusual pleckstrin homology (PH) domain, designated as the split PH domain (spPH), is both necessary and sufficient to effect activation of PLCgamma(2) by Rac2. We also demonstrate that Rac2 directly binds to PLCgamma(2) as well as to the isolated spPH of this isoform. Furthermore, through the use of NMR spectroscopy and mutational analysis, we determine the structure of spPH, define the structural features of spPH required for Rac interaction, and identify critical amino acid residues at the interaction interface. We further discuss parallels and differences between PLCgamma(1) and PLCgamma(2) and the implications of our findings for their respective signaling roles.

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Authors
Walliser, C., Retlich, M., Harris, R., Everett, K. L., Josephs, M. B., Vatter, P., Esposito, D., Driscoll, P. C., Katan, M., Gierschik, P., & Bunney, T. D.
Affiliations
  • Universität Ulm (DE)
  • Institute of Structural and Molecular Biology (GB)
  • Institute of Cancer Research (GB)
  • National Institute for Medical Research (GB)
Corresponding author
Bunney, Tom D.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2008-10
Volume
283
Issue
44
Pages
30351-30362
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m803316200
PMC
PMC2573054
OpenAlex
W2071347288
Cited by
56
References
64
Citations by year
2026: 2 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 3 · 2016: 2 · 2015: 7 · 2014: 1 · 2013: 2 · 2012: 5
FWCI
2.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
Rac2, PLCγ2, protein-protein interaction, small GTPases, PLCγ1, protein structure
MeSH terms
Animals, Blood Proteins, Chlorocebus aethiops, Humans, Models, Biological, Models, Molecular, Molecular Conformation, Phosphoproteins, Protein Binding, Signal Transduction, Gene Expression Regulation, Enzymologic, Protein Structure, Tertiary, COS Cells, Protein Isoforms, Proto-Oncogene Proteins c-akt, Phospholipase C gamma

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