The crystal structure of Escherichia coli MoeA and its relationship to themultifunctional protein gephyrin

Background: Molybdenum cofactor (Moco) biosynthesis is an evolutionarily co nserved pathway present in archaea, eubacteria, and eukaryotes. In humans, genetic abnormalities in the biosynthetic pathway result in Moco deficiency , which is accompanied by severe neurological symptoms and death shortly af ter birth. The Escherichia coli MoeA ansi MogA proteins are involved in the final step of Moco biosynthesis: the incorporation of molybdenum into moly bdopterin (MPT), the organic pyranopterin moiety of Moco. Results: The crystal structure of E, coli MoeA has been refined at 2 Angstr om resolution and reveals that the highly elongated MoeA monomer consists o f four clearly separated domains, one of which is structurally related to M ogA, indicating a divergent evolutionary relationship between both proteins . The active form of MoeA is a dimer, and a putative active site appears to be localized to a cleft formed between domain II of the first monomer and domains iii and IV of the second monomer. Conclusions: In eukaryotes, MogA and MoeA are fused into a single polypepti de chain. The corresponding mammalian protein gephyrin has also been implic ated in the anchoring of glycinergic receptors to the cytoskeleton at inhib itory synapses. Based on the structures of MoeA and MogA, gephyrin is surmi sed to be a highly organized molecule containing at least five domains. Thi s multidomain arrangement could provide a structural basis for its function al diversity. The oligomeric states of MoeA and MogA suggest how gephyrin c ould assemble into a hexagonal scaffold at inhibitory synapses.