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C2 domain

Class: Phospholipid Binding

Brief description: Approximately 130 residues, the C2 domain was first discovered as the Ca2+-binding site in conventional PKCs. Presently, more than 200 mammalian proteins contain a C2 domain. Although, most of them are involved in signal transduction [e.g., PKC, cPLA2a, PLC, plant phospholipase D (PLD), and phosphoinositide 3-kinase] or membrane trafficking (e.g., synaptotagmins, rabphilin-3A, and Munc-13), they also regulate other functions such phosphorylation of membrane proteins and, production and degradation of lipid derived second messengers. C2 domains show a lower level sequence homology as compared to C1 domains, particularly in the loop regions. Some Ca2+-independet C2 domains can bind membrane, but others participate in protein-protein interactions.

Structure:

structure Structures of many C2 domains are now available. Their analyses have indicated that all C2 domains share a common fold, with eight-stranded antiparallel beta-sandwich connected by variable loops. Three variable loops at the tip of the structure compose the Ca2+-binding sites and most Ca2+-dependent C2 domains bind two to three Ca2+ ions. In the case of cPLA2a-C2 domain that binds two loops, Ca2+-induces electrostatic neutralization that has been proposed to promote the interfacial insertion of hydrophobic and aromatic residues. Apart from elecgtrostatic switch mechanism, Ca2+ ions have also been proposed to indude conformation change and coordinate lipids through bridging. Ca2+-binding affinities are strongly dependent on the presence of phospholipids or other ligands.

Subcellular Localization:

In response to Ca2+, C2 domains translocate to the PS-rich plasma membrane (eg., C2 domain of PKC-alpha), or PC-abundant perinuclear region (eg., C2 domain of cPLA2). PtdIns(4,5)P2-binding C2 domains are found in the PtdIns(4,5)P2-rich region of the plasma membrane. The C2A domain of JFC1 is driven to the plasma membrane via PtdIns(3,4,5)P3. Also, the C2 domain of yeast ubiquitin ligase Rsp5, which binds PtdIns(3)P and PtdIns(3,5)P2, is localized at late endosomes and multivesicular bodies.

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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. Verdaguer N, Corbalan-Garcia S, Ochoa WF, Fita I, Gomez-Fernandez JC. Ca(2+) bridges the C2 membrane-binding domain of protein kinase Calpha directly to phosphatidylserine. Embo J 1999;18(22):6329-6338.

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.

5. Kohout SC, Corbalan-Garcia S, Torrecillas A, Gomez-Fernandez JC, Falke JJ. C2 domains of protein kinase C isoforms alpha, beta, and gamma: activation parameters and calcium stoichiometries of the membrane-bound state. Biochemistry 2002;41(38):11411-11424.