Mitogen activated protein kinase signaling pathways play an essential role in the cell’s response to a diverse range of stimuli. MEKK1 is a MAP3K protein that controls cell proliferation and apoptosis through the regulation of JNK and ERK pathways. MEKK1 is made up of a catalytic C-terminal kinase domain and a large N-terminal regulatory region consisting of a SWIM domain, ubiquitin-ligase (RING) domain, and TOG domain. Upon activation through distinct signals, the SWIM domain acts as a substrate receptor for RING domain ubiquitination of substrates.
To better understand how the SWIM domain may enhance ubiquitination of MEKK1 substrates, we have experimentally determined the structure of the SWIM and RING domains together through X-ray crystallography. It was found that the SWIM domain is a well-ordered mixed alpha-beta domain and directly interacts with the RING domain. The SWIM interaction occurs on the surface of the RING domain that usually binds to ubiquitin conjugating enzymes, potentially signifying the SWIM domain also plays a regulatory role on ubiquitination. Ongoing experiments are centred around mutating a key residue in the SWIM-RING interface frequently seen in cancer and determining how it affects SWIM domain function and regulation of the RING domain, and ultimately cellular regulation of MEKK1.