Structural Insights into Formation of an Active Signaling Complex between Rac and Phospholipase C Gamma 2
Open accessAbstract
Rho family GTPases are important cellular switches and control a number of physiological functions. Understanding the molecular basis of interaction of these GTPases with their effectors is crucial in understanding their functions in the cell. Here we present the crystal structure of the complex of Rac2 bound to the split pleckstrin homology (spPH) domain of phospholipase C-gamma(2) (PLCgamma(2)). Based on this structure, we illustrate distinct requirements for PLCgamma(2) activation by Rac and EGF and generate Rac effector mutants that specifically block activation of PLCgamma(2), but not the related PLCbeta(2) isoform. Furthermore, in addition to the complex, we report the crystal structures of free spPH and Rac2 bound to GDP and GTPgammaS. These structures illustrate a mechanism of conformational switches that accompany formation of signaling active complexes and highlight the role of effector binding as a common feature of Rac and Cdc42 interactions with a variety of effectors.
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PLCγ2 activation downstream of Rac is phosphorylation-independent and involves the lipid-modified, GTP-bound form of Rac.
“PLCγ2 activation downstream of Rac is phosphorylation-independent and involves the lipid-modified, GTP-bound form of Rac [73].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [73]
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- Authors
- Bunney, T. D., Opaleye, O., Roe, S. M., Vatter, P., Baxendale, R. W., Walliser, C., Everett, K. L., Josephs, M. B., Christow, C., Rodrigues-Lima, F., Gierschik, P., Pearl, L. H., & Katan, M.
- Affiliations
- Institute of Cancer Research (GB)
- Universität Ulm (DE)
- Corresponding author
- Bunney, Tom D.
- Katan, Matilda
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 34
- Issue
- 2
- Pages
- 223-233
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2066591078
- Cited by
- 72
- References
- 2
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 13 · 2019: 4 · 2016: 5 · 2015: 4 · 2014: 6 · 2013: 1 · 2012: 7
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- Rac2, PLCγ2, Rho GTPases, crystal structure, EGF signaling, PLCβ2, conformational switching
- MeSH terms
- RAC2 GTP-Binding Protein, Amino Acid Sequence, Binding Sites, Enzyme Activation, Epidermal Growth Factor, Humans, Models, Molecular, Molecular Sequence Data, Substrate Specificity, Thermodynamics, Sequence Alignment, Protein Structure, Tertiary, Crystallography, X-Ray, rac GTP-Binding Proteins, Protein Interaction Mapping, Phospholipase C gamma
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