Crystal structure of the Cys2 activator-binding domain of protein kinase Cδ in complex with phorbol ester

Zhang, Gongyi; Kazanietz, Marcelo G.; Blumberg, Peter M.; Hurley, James H.

doi:10.1016/0092-8674(95)90011-x

Cited by 644 publications

(912 citation statements)

References 26 publications

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“…More than 30 different mammalian proteins contain the C1 domain, and most of them have been shown to bind DAG and phorbol ester. The X-ray crystal structure of the PKCy C1B domain shows that it has unique structural features that are consistent with its membrane binding mechanism (6). The domain has a polar binding pocket for DAG/phorbol ester located at the tip of the molecule.…”

Section: C1 Domainsmentioning

confidence: 64%

Lipid binding domains: more than simple lipid effectors

Stahelin

2009

Journal of Lipid Research

123

105

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The spatial and temporal regulation of lipid molecules in cell membranes is a hallmark of cellular signaling and membrane trafficking events. Lipid-mediated targeting provides for strict control and versatility, because cell membranes harbor a large number of lipid molecules with variation in head group and acyl chain structures. Signaling and trafficking proteins contain a large number of modular domains that exhibit specific lipid binding properties and play a critical role in their localization and function. Nearly 20 years of research including structural, computational, biochemical and biophysical studies have demonstrated how these lipid-binding domains recognize their target lipid and achieve subcellular localization. The integration of this individual lipid-binding domain data in the context of the fulllength proteins, macromolecular signaling complexes, and the lipidome is only beginning to be unraveled and represents a target of therapeutic development. This review brings together recent findings and classical concepts to concisely summarize the lipid-binding domain field while illustrating where the field is headed and how the gaps may be filled in with new technologies.-Stahelin, R. V. Lipid binding domains: more than simple lipid effectors. J. Lipid Res. 2009. 50: S299-S304.

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Section: C1 Domainsmentioning

confidence: 64%

Lipid binding domains: more than simple lipid effectors

Stahelin

2009

Journal of Lipid Research

123

105

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“…In addition, the fact that SRBC binds to phosphatidylserine suggests that phosphatidylserine mediates or stabilizes the interaction between SRBC and PKC␦ through its bridging. Interaction with SRBC was also observed for MCD209, a deletion mutant of PKC␦ lacking the kinase domain and the C-terminal half of the cysteine-rich domain that is responsible for the binding to phorbol ester or diacylglycerol (32,33). This indicates that these functional domains are dispensable for the interaction with SRBC.…”

Section: Phosphatidylserine Binds To Srbc and Clone 53 Product-mentioning

confidence: 66%

A Protein Kinase Cδ-binding Protein SRBC Whose Expression Is Induced by Serum Starvation

Izumi

Hirai

Tamai

et al. 1997

Journal of Biological Chemistry

104

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West-Western screening of a cDNA expression library using 32 P-labeled, autophosphorylated protein kinase C␦ (PKC␦) as a probe, led us to identify cDNA clones encoding a PKC␦-binding protein that contains a leucine zipper-like motif in its N-terminal region and two PEST sequences in its C-terminal region. This protein shows overall sequence similarity (43.3%) to the serum deprivation response (sdr) gene product, and we named it SRBC (sdr-related gene product that binds to c-kinase). PKC␦ binds to the C-terminal half of SRBC through the regulatory domain and phosphorylates it in vitro. In COS1 cells, the phosphorylation of over-expressed SRBC is stimulated by 12-O-tetradecanoylphorbol-13-acetate and further enhanced by the over-expression of PKC␦. The mRNA for SRBC is detected in a wide variety of cultured cell lines and tissues and is strongly induced by serum starvation. Furthermore, SRBC mRNA is induced during retinoic acid-induced differentiation of P19 cells. These results suggest that SRBC serves as a substrate and/or receptor for PKC and might be involved in the control of cell growth mediated by PKC.

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“…It is also possible that the C1 domain of mRas-GRP is binding another lipid that is generated in response to PC-PLC treatment and colocalizes with diacylglycerol in these structures. However, the major products of diacylglycerol metabolism, such as phosphatidylcholine, tri-and mono-acylglycerols, and fatty acids (14,50), are not expected to bind the C1 domain of mRasGRP, given the size and hydrophobicity of the residues predicted to compose its ligand-binding pocket (33,64). PC-PLC had no obvious effect on the distribution of mRasGRP or the C1 domains during the first 15 min of treatment, even though activation of ERK1 and ERK2 (presumably via diacylglycerol-mediated activation of PKCs) was occurring during this time.…”

Section: Vol 18 1998 C1 Domain-mediated Regulation Of Rasgrp 7001mentioning

confidence: 99%

Regulation of RasGRP via a Phorbol Ester-Responsive C1 Domain

Tognon

Kirk

Passmore

et al. 1998

Molecular and Cellular Biology

219

207

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As part of a cDNA library screen for clones that induce transformation of NIH 3T3 fibroblasts, we have isolated a cDNA encoding the murine homolog of the guanine nucleotide exchange factor RasGRP. A point mutation predicted to prevent interaction with Ras abolished the ability of murine RasGRP (mRasGRP) to transform fibroblasts and to activate mitogen-activated protein kinases (MAP kinases). MAP kinase activation via mRasGRP was enhanced by coexpression of H-, K-, and N-Ras and was partially suppressed by coexpression of dominant negative forms of H-and K-Ras. The C terminus of mRasGRP contains a pair of EF hands and a C1 domain which is very similar to the phorbol ester-and diacylglycerol-binding C1 domains of protein kinase Cs. The EF hands could be deleted without affecting the ability of mRasGRP to transform NIH 3T3 cells. In contrast, deletion of the C1 domain or an adjacent cluster of basic amino acids eliminated the transforming activity of mRasGRP. Transformation and MAP kinase activation via mRasGRP were restored if the deleted C1 domain was replaced either by a membrane-localizing prenylation signal or by a diacylglycerol-and phorbol ester-binding C1 domain of protein kinase C. The transforming activity of mRasGRP could be regulated by phorbol ester when serum concentrations were low, and this effect of phorbol ester was dependent on the C1 domain of mRasGRP. The C1 domain could also confer phorbol myristate acetate-regulated transforming activity on a prenylation-defective mutant of K-Ras. The C1 domain mediated the translocation of mRasGRP to cell membranes in response to either phorbol ester or serum stimulation. These results suggest that the primary mechanism of activation of mRasGRP in fibroblasts is through its recruitment to diacylglycerolenriched membranes. mRasGRP is expressed in lymphoid tissues and the brain, as well as in some lymphoid cell lines. In these cells, RasGRP has the potential to serve as a direct link between receptors which stimulate diacylglycerol-generating phospholipase Cs and the activation of Ras.

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Crystal structure of the Cys2 activator-binding domain of protein kinase Cδ in complex with phorbol ester

Cited by 644 publications

References 26 publications

Lipid binding domains: more than simple lipid effectors

Lipid binding domains: more than simple lipid effectors

A Protein Kinase Cδ-binding Protein SRBC Whose Expression Is Induced by Serum Starvation

Regulation of RasGRP via a Phorbol Ester-Responsive C1 Domain

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