Structural anatomy of C1 domain interactions with DAG and other agonists

Abstract

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. 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) as the first member of the DAG effector cohort. Herein, we report the first high-resolution crystal structures of a C1 domain (C1B from PKCdelta) 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.

TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis

“…PKC isoforms belongs to one of three classes, which are conventional (α, β, and γ), novel (δ, ε, η, and θ), and atypical (ζ and ι/λ). Conventional and novel PKCs have a C1 domain that binds to bryo-1, TPPB, and endogenous diacylglycerol (DAG), but atypical PKCs do not (Das and Rahman, 2014;Katti et al, 2022). Currently, it is unknown which isoform(s) is involved in anti-inflammatory and regenerative effects in microglia and CNS-associated macrophages.…”

Novel Skeletal Rearrangements of the Tigliane Diterpenoid Core

“…This functionality, acting as a hydrogen-bonding donor/acceptor, has the potential to perturb the delicate network of hydrogen bondings involving the oxygenated functions at C-20, a critical element for binding of phorbol esters to PKC. 14 oxidative fragmentations of the diterpenoid. 15 Therefore, the preparation of 5-dehydro tigilanol tiglate(3a) (Chart 1) was perceived as critical for the study of the structure−activity relationships of epoxytiglianes.…”