C1 domains exposed: From diacylglycerol binding to protein–protein interactions

doi:10.1016/j.bbalip.2006.05.001

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Volume 1761, Issue 8, August 2006, Pages 827-837

https://doi.org/10.1016/j.bbalip.2006.05.001 Get rights and content

Abstract

C1 domains, cysteine-rich modules originally identified in protein kinase C (PKC) isozymes, are present in multiple signaling families, including PKDs, chimaerins, RasGRPs, diacylglycerol kinases (DGKs) and others. Typical C1 domains bind the lipid second messenger diacylglycerol (DAG) and DAG-mimetics such as phorbol esters, and are critical for governing association to membranes. On the contrary, atypical C1 domains possess structural determinants that impede phorbol ester/DAG binding. C1 domains are generally expressed as twin modules (C1A and C1B) or single domains. Biochemical and cellular studies in PKC and PKD isozymes revealed that C1A and C1B domains are non-equivalent as lipid-binding motifs or translocation modules. It has been recently determined that individual C1 domains have unique patterns of ligand recognition, driven in some cases by subtle structural differences. Insights from recent 3-D studies on β2-chimaerin and Munc13-1 revealed that their single C1 domains are sterically blocked by intramolecular interactions, suggesting that major conformational changes would be required for exposing the site of DAG interaction. Thus, it is clear that the protein context plays a major role in determining whether binding of DAG to the C1 domain would lead to enzyme activation or merely serves as an anchoring mechanism.

Introduction

C1 domains are small structural units of approximately 50 amino acids that were originally discovered as lipid-binding modules in protein kinase Cs (PKCs), a family of related kinases that regulate proliferation, differentiation and malignant transformation. Alignment of PKC cDNAs after their isolation in the 1980s revealed four conserved domains: the C1 and C2 domains in the N-terminal regulatory region, and the C3 and C4 domains in the C-terminal catalytic (kinase) region. It became clear that C1 domains were involved in the recognition of the phorbol ester tumor promoters and diacylglycerol (DAG), a lipid second messenger that is generated in the plasma membrane as a consequence of the activation of seven-transmembrane receptors or tyrosine-kinases that couple to phospholipase C (PLC) isoforms. Based on their biochemical properties, PKC isozymes have been classified into 3 groups: the “classical” or “conventional” PKCs (cPKCs) which comprise PKCα, βI, βII, and γ; the “novel” PKCs (nPKCs), a group that includes PKCδ, PKCε, PKCη, and PKCθ; and the “atypical” PKCs (aPKCs) which comprise PKCζ and PKCι/λ. This classification was based on the biochemical properties of the different isozymes: while both cPKCs and nPKCs are sensitive to DAG and phorbol esters, only cPKCs are activated by calcium; aPKCs are insensitive to DAG and calcium [1], [2], [3].

C1 domains in PKCs have the characteristic motif HX₁₂CX₂CX_nCX₂CX₄HX₂CX₇C, where H is histidine, C is cysteine, X is any other amino acid, and n is 13 or 14. While the motif is duplicated in tandem in cPKCs and nPKCs, a single copy is present in members of the aPKC family. In addition to PKC isozymes, other molecules possess C1 domains in their structure [4]. Two copies of the motif are present in protein kinase D (PKD) isoforms and diacylglycerol kinases (DGKs). Examples of molecules with a single C1 domain include kinases (c-Raf, Kinase Suppressor of Ras or KSR), regulators of small G-proteins (chimaerin Rac-GAPs, RasGRP GEFs, Vav), and molecules involved in vesicle release from synaptic terminals (Munc13). Due to the resemblance of C1 domains to DNA-binding regions of transcription factors rich in cysteines, early studies called this motif “zinc fingers”, “cysteine-rich-regions”, or “cysteine-rich motifs”. However, C1 domains have an entirely different structure and do not bind to DNA. The consensus now is to call any domain homologous to a single cysteine-rich repeat of PKC a C1 domain, regardless of function and context (Table 1). If twin domains occur in the same molecule, they are designated C1A and C1B [5].

C1 domains play a crucial role in targeting PKCs and other molecules from the cytosol to membranes (“translocation”) both in response to phorbol esters or DAG generated upon receptor activation. Lipid binding to the C1 domain represents a crucial step in the allosteric activation of PKCs and subsequent phosphorylation of PKC substrates [6], [7], [8]. Studies using isolated C1 domains fused to GFP allowed for the visualization of this redistribution in response to phorbol esters or receptor activation. Photobleaching recovery analysis revealed that a lipophilic phorbol ester (phorbol 12-myristate 13-acetate or PMA) nearly immobilized the C1 domain in the membrane, whereas the shorter chain DAG mimetic DiC8 leaves the domain diffusible within the membrane, suggesting a contribution of acyl chains to membrane insertion [9], [10], as it was well established with the full-length enzyme [11].

Section snippets

The C1 domain as a phorbol ester/DAG binding module: historical perspectives

Understanding the mechanisms of PKC activation represented a major challenge since its discovery in the 1970s. Several laboratories, including those of Peter M. Blumberg in the United States and Yasutomi Nishizuka in Japan, established that PKC is a major cellular receptor for phorbol esters, natural products that were extensively characterized as tumor promoters. The Blumberg lab was instrumental in developing a highly sensitive binding assay based on the use of the radioligand [³H]phorbol 12,

Lessons from the PKCδ C1B domain 3-D structure

The first structure of a C1 domain became available in 1994 from NMR spectroscopy analysis of the PKCα C1B domain [28]. This study revealed that the domain adopts a globular fold in which two separate Zn²⁺-binding sites are formed by two non-contiguous areas of the primary sequence. Comprehensive information on C1 domain-phorbol ester interactions was gained by co-crystallization of the PKCδ C1B domain with phorbol 13-acetate [29]. These studies provided important insights into the nature of

Typical vs. atypical C1 domains

The presence of a C1 domain does not necessarily imply phorbol ester/DAG responsiveness, as initially demonstrated for the atypical PKCs. The lack of [³H]PDBu binding in PKCζ was originally ascribed to the absence of Pro 11 in the consensus sequence. However, introducing a Pro in that position does not restore phorbol ester binding, suggesting that other essential structural features were missing in the PKCζ C1 domain [31]. The proto-oncogene c-Raf and other proteins such as KSR and Lfc also

Non-equivalency of C1A and C1B domains

An issue still subject to debate is whether C1A and C1B domains in PKCs have equivalent roles. Early studies by Riedel and co-workers using yeast as an experimental model suggested differential roles for PKCα C1 domains in the control of cell growth in response to ligands [45], [46]. In those assays, PMA was found to regulate PKCα activity via either C1 domain, while mezerein predominantly acts via the C1A domain. Subsequent biochemical and functional analyses from several laboratories provided

The interplay between C1 and C2 domains

Several studies on PKC isozymes suggest a C2–C1 domain sequential model for PKC activation [61]. Newton and co-workers found that both C1 and C2 domains in PKCβII possess elements for membrane targeting [8]. The Cho laboratory found that the PKCα C2 domain interacts with anionic lipids in a calcium-dependent manner and the C1 domain confers the selectivity for PS and phorbol ester/DAG binding [62]. This sequential model proposes that the C2 domain is involved in the initial calcium and

C1 domains in “non-kinase” phorbol ester receptors as DAG sensors

n-chimaerin (later re-named α1-chimaerin), was discovered in the early 1990s as the first phorbol ester receptor unrelated to PKC [21], [65]. Additional members of the chimaerin family (α2, β1, and β2) were later identified [66], [67]. The zebrafish homologue of chimaerins has been recently characterized as a phorbol ester receptor that play a role in early development [68]. C. elegans Unc-13, its mammalian homologs Munc13s, and RasGRPs were also found to bind [³H]PDBu with high affinity in the

“Exposed” vs. “non-exposed” C1 domains: insights from the β2-chimaerin crystal structure

While important information has been gained at the biochemical and biophysical levels with purified PKCs and individual C1 domains, the lack of a 3-D structure for intact PKCs has represented a major limitation for understanding in detail the molecular aspects of their activation. The recent determination of the crystal structure of β2-chimaerin has provided important insights into the mechanisms of lipid activation via C1 domains [83]. A striking finding was that the C1 domain in β2-chimaerin

Rational synthesis of C1 domain ligands: is it possible to achieve selectivity?

Natural products that bind with high affinity to C1 domains have provided the initial framework for the development of PKC activators. Ligands as diverse as phorbol esters, bryostatins, indolactams, or ingenols all bind to PKCs, PKDs, chimaerins, and RasGRPs despite their diverse structure. However, structure–activity relationships revealed a differential pattern of recognition. So far, the largest difference in sensitivity for C1 domain ligands has been observed for thymeleatoxin, a mezerein

The C1 domain: a protein-interaction module?

Increasing evidence suggests that the C1 domain can also act as a protein-interaction module. Several PKC-interacting proteins that associate with the C1 domain have been identified, which modulate either activity or cellular localization. The cell matrix protein fascin was shown to interact with the C1B domain of PKCα [93]. This interaction is dependent on PKCα activity, and inhibition of this association leads to increased cell migration on fibronectin and fascin protrusions, suggesting that

Acknowledgements

The laboratory of M.G.K. is supported by grants from NIH. F.C-G. is supported by a Minority Supplement from NCI. M.G.K. wants to dedicate this review to Dr. Peter M. Blumberg (NIH) for his outstanding contributions to the field, mentoring and friendship.

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ReviewC1 domains exposed: From diacylglycerol binding to protein–protein interactions

Abstract

Introduction

Section snippets

The C1 domain as a phorbol ester/DAG binding module: historical perspectives

Lessons from the PKCδ C1B domain 3-D structure

Typical vs. atypical C1 domains

Non-equivalency of C1A and C1B domains

The interplay between C1 and C2 domains

C1 domains in “non-kinase” phorbol ester receptors as DAG sensors

“Exposed” vs. “non-exposed” C1 domains: insights from the β2-chimaerin crystal structure

Rational synthesis of C1 domain ligands: is it possible to achieve selectivity?

The C1 domain: a protein-interaction module?

Acknowledgements

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Review
C1 domains exposed: From diacylglycerol binding to protein–protein interactions