Structural anatomy of C1 domain interactions with DAG and other agonists

Diacylglycerol (DAG) is a versatile lipid whose 1,2- sn -stereoisomer serves both as second messenger in signal transduction pathways that control vital cellular processes, and as metabolic precursor for downstream signaling lipids such as phosphatidic acid[1][1],[2][2]. DAG effector proteins compete for available lipid using conserved homology 1 (C1) domains as DAG-sensing modules. Yet, how C1 domains recognize and capture DAG in the complex environment of a biological membrane has remained unresolved for the 40 years since the discovery of Protein Kinase C (PKC)[3][3] as the first member of the DAG effector cohort. Herein, we report the first high-resolution crystal structures of a C1 domain (C1B from PKCδ) complexed to DAG and to each of four potent PKC agonists that produce different biological readouts and that command intense therapeutic interest. This structural information details the mechanisms of stereospecific recognition of DAG by the C1 domains, the functional properties of the lipid-binding site, and the identities of the key residues required for the recognition and capture of DAG and exogenous agonists. Moreover, the structures of the five C1 domain complexes provide the high-resolution guides for the design of agents that modulate the activities of DAG effector proteins. ### Competing Interest Statement The authors S.S.K. and T.I.I. declare the existence of a potential financial interest due to a provisional patent application pending with the United States Patent and Trademark Office, with the specific aspect of this manuscript covered in the application being the method of crystallization of C1 domains complexed to ligands (T.I.I. and S.S.K. are listed as inventors and applicants, under obligation to assign to Texas A&M University). All other authors declare no competing interests. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3