The inter-dimeric interface controls function and stability of Ureaplasma urealiticum methionine S-adenosyltransferase
Methionine S-adenosyltransferases (MATs) are predominantly homotetramers, comprised of dimers of dimers. The highly conserved dimeric interface harbors two active sites, making the dimer the obligatory functional unit. Yet, functionality of the recently evolved inter-dimeric interface remains unknown. Here, we show that the inter-dimeric interface of U. urealiticum MAT has evolved to control the catalytic activity and structural integrity of the homotetramer in response to product accumulation. When all four active sites are occupied with the product, S-adenosylmethionine (SAM), binding of four additional SAM molecules to the inter-dimeric interface prompts a [~]45{degrees} shift in the dimer orientation and a concomitant [~]60% increase in the interface area. This rearrangement inhibits the enzymatic activity by locking the flexible active site loops in a closed state and renders the tetramer resistant to proteolytic degradation. Our findings suggest that the inter-dimeric interfaces of MATs are recruited by evolution to tune the molecular properties of the entire homotetramer.