Ubiquitin‐fold protein and JAMM/MPN+ metalloprotease constitute a regulating system for enzyme inhibition and activation (931.1)

Abstract

Molybdenum cofactor (Moco) is essential for diverse enzymes to form the catalytic center. Moco biosynthesis is a conserved pathway existent in all three life domains, and Moco biosynthesis deficiency in humans causes serious disease. Molybdopterin (MPT) synthase catalyzes the biosynthesis of MPT, a precursor of Moco. Crystal structures of MPT synthase have been reported for over 10 years; however, its post‐translational regulation is poorly known. Here we report a MPT synthase inhibiting and activating mechanism by using the archaeon Haloferax volcanii as a model. We provide strong evidence that the MPT synthase activity is inhibited by SAMP1 (an ubiquitin‐fold protein homolog of the small subunit of MPT synthase, MoaD) covalent linkage to MoaE (a homolog of the large subunit of MPT synthase). Furthermore, we show that the JAMM/MPN+ metalloprotease HvJAMM1 is required to cleave covalently linked inactive SAMP1‐MoaE to free SAMP1 and MoaE, which suggests activation of MPT synthase. Since SAMP1 is an ubiquitin‐fold small protein, our research also indicates a broad idea that ubiquitin‐fold proteins can inhibit an enzyme by linking to its active site and that a protease, like HvJAMM1, can cleave this linkage and reactivate the enzyme.Grant Funding Source: NIH R01 GM057498 and DOE DE‐FG02‐05ER15650