MEKK1 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase kinase 1] is a MAP3K (MAPK kinase kinase) that regulates MAPK activation, and is the only known mammalian kinase that is also a ubiquitin ligase. MEKK1 contains a RING domain within its N-terminal regulatory region, and MEKK1 has been shown to ubiquitylate the AP-1 (activator protein 1) transcription factor protein c-Jun, but the mechanism by which MEKK1 interacts with c-Jun to induce ubiquitylation has not been defined. Proximal to the RING domain is a SWIM (SWI2/SNF2 and MuDR) domain of undetermined function. In the present study, we demonstrate that the MEKK1 SWIM domain, but not the RING domain, directly associates with the c-Jun DNA-binding domain, and that the SWIM domain is required for MEKK1-dependent c-Jun ubiquitylation. We further show that this MEKK1 SWIM–Jun interaction is specific, as SWIM domains from other proteins failed to bind c-Jun. We reveal that, although the Jun and Fos DNA-binding domains are highly conserved, the MEKK1 SWIM domain does not bind Fos. Finally, we identify the sequence unique to Jun proteins required for specific interaction with the MEKK1 SWIM domain. Therefore we propose that the MEKK1 SWIM domain represents a novel substrate-binding domain necessary for direct interaction between c-Jun and MEKK1 that promotes MEKK1-dependent c-Jun ubiquitylation.

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