C1 domains exposed: from diacylglycerol binding to protein-protein interactions.
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 beta2-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.
Colón-González
Francheska
F
Department of Pharmacology, University of Pennsylvania School of Medicine, 816 Biomedical Research Building II/III, 421 Curie Blvd., Philadelphia, PA 19104-6160, USA.
Kazanietz
Marcelo G
MG
D000595:Amino Acid Sequence; D000818:Animals; D020740:Chimerin Proteins / Q000737:chemistry; D019852:Diacylglycerol Kinase / Q000737:chemistry; D004075:Diglycerides / Q000737:chemistry*; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010703:Phorbol Esters / Q000737:chemistry; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry*; D051745:Protein Kinase C-delta / Q000737:chemistry* / Q000235:genetics; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011955:Receptors, Drug / Q000737:chemistry*
D020740:Chimerin Proteins; D004075:Diglycerides; D007527:Isoenzymes; D010703:Phorbol Esters; D011955:Receptors, Drug; C027776:phorbol ester receptor; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D051745:Protein Kinase C-delta