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Diacylglycerol(DAG)represents one of the central second messengers in the cell that regulates signals crucial to the control of immune responses,neuron communication,and phagocytosis.DAG signals by binding and activating C1 domain-containing proteins such as PKCs,PKDs,chimaerins,and RasGRPs.The C1 domains of protein kinase C(PKC)isozymes provide the paradigm for the DAG-responsive C1 domains.The structural information currently available for C1 domains,however,provides too few details to sketch a molecular mechanism of the domains in capturing DAG molecules.Here we report the results of the systems complsed of the C1A domain in human PKC and several mixed lipid-bilayers obtained from a combined coarse-grained and all-atom molecular dynamics simulations.It was found that C1A keeps its globular structure when contacting with a lipid bilayer consisting of DOPC and DAG molecules,while the globular structure is damaged when DOPC molecules are replaced by DOPE molecules.The combination of C1A with the lipid bilayer carses a negative curvature on the bilayer surface,which in turn drives DAG molecules to move to C1A.Meanwhile,several hydrophobic loops in C1A stay undemeath the membrane surface and fulfill the function of capturing DAG ligands.It was also demonstrated that the interaction between C1A and lipid bilayers is largely attenuated when DAGs are removed from the system,indicating that DAGs play a key role in targeting C1 domains to bio-membranes.