Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module
Yi‐Chuan Li, Ti‐Chun Chao, Hee Jong Kim, Timothy Cholko, Shin-Fu Chen, Guojie Li, Laura Snyder, Kotaro Nakanishi, Chia‐en A. Chang, Kenji Murakami, Benjamin A. García, Thomas Boyer, Kuang‐Lei Tsai
Abstract
CKM that redefines prior CKM structural models and explains the mechanism of Med12-dependent Cdk8 activation. Med12 interacts extensively with CycC and activates Cdk8 by stabilizing its activation (T-)loop through conserved Med12 residues recurrently mutated in human tumors. Unexpectedly, Med13 has a characteristic Argonaute-like bi-lobal architecture. These findings not only provide a structural basis for understanding CKM function and pathological dysfunction, but also further impute a previously unknown regulatory mechanism of Mediator in transcriptional modulation through its Med13 Argonaute-like features.