Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
Biomedical Sciences Graduate Program, University of California, La Jolla, California, USA.
IUBMB Life. 2020 Dec;72(12):2584-2590. doi: 10.1002/iub.2401. Epub 2020 Nov 9.
Protein kinase C (PKC) family members are multi-domain proteins whose function is exquisitely tuned by interdomain interactions that control the spatiotemporal dynamics of their signaling. Despite extensive mechanistic studies on this family of enzymes, no structure of a full-length enzyme that includes all domains has been solved. Here, we take into account the biochemical mechanisms that control autoinhibition, the properties of each individual domain, and previous structural studies to propose a unifying model for the general architecture of PKC family members. This model shows how the C2 domains of conventional and novel PKC isozymes, which have different topologies and different positions in the primary structure, can occupy the same position in the tertiary structure of the kinase. This common architecture of conventional and novel PKC isozymes provides a framework for understanding how disease-associated mutations impair PKC function.
蛋白激酶 C（PKC）家族成员是多结构域蛋白，其功能通过控制信号转导的时空动态的结构域间相互作用来进行精细调节。尽管对该酶家族进行了广泛的机制研究，但尚未解决包含所有结构域的全长酶的结构。在这里，我们考虑了控制自身抑制的生化机制、每个单独结构域的特性以及先前的结构研究，以提出 PKC 家族成员的通用结构的统一模型。该模型展示了具有不同拓扑结构和在一级结构中不同位置的传统和新型 PKC 同工酶的 C2 结构域如何能够占据激酶三级结构中的相同位置。传统和新型 PKC 同工酶的这种通用结构为理解与疾病相关的突变如何损害 PKC 功能提供了一个框架。
