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Diacylglycerol (DAG) is an important second messenger. Phorbol esters (PE) are analogues of DAG and potent tumor promoters that cause a variety of physiological changes when administered to both cells and tissues. DAG activates a family of serine/threonine protein kinases, collectively known as protein kinase C (PKC) [1]. Phorbol esters can directly stimulate PKC. The N-terminal region of PKC, known as C1, has been shown [2] to bind PE and DAG in a phospholipid and zinc-dependent fashion. The C1 region contains one or two copies (depending on the isozyme of PKC) of a cysteine-rich domain about 50 amino-acid residues long and essential for DAG/PE-binding. Such a domain has also been found in the following proteins:

• Diacylglycerol kinase (EC 2.7.1.107) (DGK) [3], the enzyme that converts DAG into phosphatidate. It contains two copies of the DAG/PE-binding domain in its N-terminal section. At least five different forms of DGK are known in mammals.
• N-chimaerin. A brain specific protein which shows sequence similarities with the BCR protein at its C-terminal part and contains a single copy of the DAG/PE-binding domain at its N-terminal part. It has been shown [4,5] to be able to bind phorbol esters.
• The raf/mil family of serine/threonine protein kinases. These protein kinases contain a single N-terminal copy of the DAG/PE-binding domain.
• The unc-13 protein from Caenorhabditis elegans. Its function is not known but it contains a copy of the DAG/PE-binding domain in its central section and has been shown to bind specifically to a phorbol ester in the presence of calcium [6].
• The vav oncogene. Vav was generated by a genetic rearrangement during gene transfer assays. Its expression seems to be restricted to cells of hematopoeitic origin. Vav seems [5,7] to contain a DAG/PE-binding domain in the central part of the protein.
• The Drosophila GTPase activating protein rotund.

The DAG/PE-binding domain binds two zinc ions; the ligands of these metal ions are probably the six cysteines and two histidines that are conserved in this domain. We have developed both a signature pattern and a profile that span completely the DAG/PE domain.

May 2004 / Text revised.

PROSITE methods (with tools and information) covered by this documentation:

ZF_DAG_PE_2, PS50081; Zinc finger phorbol-ester/DAG-type profile  (MATRIX)

Sequences known to belong to this class detected by the profile: ALL, except 3 Other sequence(s) detected in Swiss-Prot: NONE.

• Domain architecture view of Swiss-Prot proteins matching PS50081 • Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS50081 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS50081 • Scan Swiss-Prot/TrEMBL entries against PS50081 • view ligand binding statistics

Matching PDB structures: 1FAQ 1FAR 1KBE 1KBF ... [ALL]

ZF_DAG_PE_1, PS00479; Zinc finger phorbol-ester/DAG-type signature  (PATTERN)

Consensus pattern: H-x-[LIVMFYW]-x(8,11)-C-x(2)-C-x(3)-[LIVMFC]-x(5,10)-C-x(2)-C-x(4)-[HD]-x(2)-C-x(5,9)-C The 6 C's and the 2 H's are involved in binding Zinc Sequences known to belong to this class detected by the pattern: ALL, except a few DGK's Other sequence(s) detected in Swiss-Prot: NONE.

• Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS00479 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS00479 • Scan Swiss-Prot/TrEMBL entries against PS00479 • view ligand binding statistics

Matching PDB structures: 1FAQ 1FAR 1KBE 1KBF ... [ALL]

1	Authors	Azzi A., Boscoboinik D., Hensey C.
	Title	The protein kinase C family.
	Source	Eur. J. Biochem. 208:547-557(1992).
	PubMed ID	1396661

2	Authors	Ono Y., Fujii T., Igarashi K., Kuno T., Tanaka C., Kikkawa U., Nishizuka Y.
	Title	Phorbol ester binding to protein kinase C requires a cysteine-rich zinc-finger-like sequence.
	Source	Proc. Natl. Acad. Sci. U.S.A. 86:4868-4871(1989).
	PubMed ID	2500657

3	Authors	Sakane F., Yamada K., Kanoh H., Yokoyama C., Tanabe T.
	Title	Porcine diacylglycerol kinase sequence has zinc finger and E-F hand motifs.
	Source	Nature 344:345-348(1990).
	PubMed ID	2156169

4	Authors	Ahmed S., Kozma R., Monfries C., Hall C., Lim H.H., Smith P., Lim L.
	Title	Human brain n-chimaerin cDNA encodes a novel phorbol ester receptor.
	Source	Biochem. J. 272:767-773(1990).
	PubMed ID	2268301

5	Authors	Ahmed S., Kozma R., Lee J., Monfries C., Harden N., Lim L.
	Title	The cysteine-rich domain of human proteins, neuronal chimaerin, protein kinase C and diacylglycerol kinase binds zinc. Evidence for the involvement of a zinc-dependent structure in phorbol ester binding.
	Source	Biochem. J. 280:233-241(1991).
	PubMed ID	1660266

6	Authors	Ahmed S., Maruyama I.N., Kozma R., Lee J., Brenner S., Lim L.
	Title	The Caenorhabditis elegans unc-13 gene product is a phospholipid-dependent high-affinity phorbol ester receptor.
	Source	Biochem. J. 287:995-999(1992).
	PubMed ID	1445255

7	Authors	Boguski M.S., Bairoch A., Attwood T.K., Michaels G.S.
	Title	Proto-vav and gene expression.
	Source	Nature 358:113-113(1992).
	PubMed ID	1614545
	DOI	10.1038/358113a0

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