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C1 Domain
Class:Phospholipid Binding

No ImageThe crystal structure of the second cysteine rich domain of PKCd reveals the upper region of the domain contains two beta-sheets, which are pulled apart to form a cavity, and a short C-terminal alpha-helix. In the absence of ligand the cavity formed between the two beta-sheets is lined with water. Phorbol ester is able to fit into the cavity between the beta-sheets and displace a water molecule. The C3, C4 and C20 oxygens of phorbol ester are able to replace the lost hydrogen bonds after water removal. Phorbol ester binding presents a continuous hydrophobic cap allowing this region to be buried into membranes. Little conformational change is associated with phorbol ester binding to the C1 domain.

Structure Reference:
Zhang, G. et al. (1995) Cell. 81(6):917-24. PDB: 1PTQ.

Domain binding and function:
C1 domains are approximately 50 amino acids long, enriched in cysteines, and are involved in the recruitment of proteins to the membrane. Typically, C1 domains bind phorbol esters or diacylglycerol (DAG), which are necessary for membrane localization. With phorbol ester bound, the upper surface of the C1 domain forms a contiguous hydrophobic surface in the domain. This enables the region to be buried into the lipid bilayer stabilizing membrane insertion. The middle portion of the domain contains a number of basic residues that can interact with lipid headgroups in the membrane, while the lower half of the C1 domain contains two zinc-binding sites that are important to maintain the fold of the domain. The two major classes of C1 domain containing proteins are protein kinase C (PKC) isozymes and chimaerins. Chimaerins, or "non-kinase" phorbol ester receptors, are Rac-GAPs that are lipid-regulated via their C1 domain.
Examples of Proteins: 
C1 domain protein
Binding partner
PKC isoforms (classical and novel) diacylglycerol or phorbol esters
Diacylglycerol kinase diacylglycerol or phorbol esters
c-Raf Ser/Thr Kinase diacylglycerol or phorbol esters
n-chimaerin (Rac GTPase activating proteinP) diacylglycerol or phorbol esters

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