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C1 Domain                   

Class: Phospholipid Binding

Brief description: The C1 domain was first identified as the interaction site for DAG and its functional analogue, phorbol ester, in PKCs. It is a cysteine-rich compact structure and is approximately 50 amino acids long. Solution of C1 domain of PKC-delta revealed short beta-strands, one short a-helix, and two zinc ions. DAG/phorbol ester-binding C1 domains have been subsequently found in other proteins performing variety of functions. They genrally show a high sequence homology. However, minor sequence variations in the ligand-binding region dramatically affect affinity for DAG and phorbol ester. More than 50 different mammalian proteins in the current protein database contain the C1 domain; among these C1 domains, many have been shown to bind DAG/Phorbol ester.

Structure:

structure At the tip of the molecule is located a polar binding pocket for DAG/phorbol ester which is is surrounded by hydrophobic and aromatic residues. A ring of cationic residues in the middle part of the molecule adjoins these hydrphobic/aromatic residues. The crystal structure of the second cysteine rich domain of PKC-delta reveals the upper region of the domain contains two beta-sheets. A cavity is formed by pulling these sheets apart. This cavity is lined with water in the absence of the ligand. Phorbol ester fits into the cavity between the beta-sheets by displacing the water molecules.

Subcellular Localization:

C1 domains usually localize mostly in response to DAG and phorbol esters. They are recruited to the plasma membrane in response to phorbol 12-myristate 13-acetate (PMA) or stimuli that induce DAG because DAG and PMA are present in the membranes.

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Relevant Literature

1. Cho W. Membrane targeting by C1 and C2 domains. J Biol Chem 2001;276(35):32407-32410.

2. Cho W, Stahelin RV. Membrane-protein interactions in cell signaling and membrane trafficking. Annu Rev Biophys Biomol Struct 2005;34:119-151.

3. Stahelin RV, Digman MA, Medkova M, Ananthanarayanan B, Rafter JD, Melowic HR, Cho W. Mechanism of diacylglycerol-induced membrane targeting and activation of protein kinase Cdelta. J Biol Chem 2004;279(28):29501-29512.

4. Newton AC, Johnson JE. Protein kinase C: a paradigm for regulation of protein function by two membrane-targeting modules. Biochim Biophys Acta 1998;1376(2):155-172.