MgATP Regulates Allostery and Fiber Formation in IMPDHs

This work was supported in part by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé Et de la Recherche Médicale (INSERM), theConseil Régional d'Ile-de-France (Chemical Library Project, grant nos. I 06- 222/R and I 09-1739/ R, which included a postdoctoral fellowship for I.S.-A.) and the French Infrastructure for Integrated Structural Biology (FRISBI) ANR- 10-INSB-05-01. T.A. was a recipient of a PhD fellowship from the Conseil Régional d'Ile-de-France and the ''D.I.M. maladies infectieuses, parasitaires et nosocomiales émergentes'' 2011; International audience; Inosine-5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in nucleotide biosynthesis studied as an important therapeutic target and its complex functioning in vivo is still puzzling and debated. Here, we highlight the structural basis for the regulation of IMPDHs by MgATP. Our results demonstrate the essential role of the CBS tandem, conserved among almost all IMPDHs. We found that Pseudomonas aeruginosa IMPDH is an octameric enzyme allosterically regulated by MgATP and showed that this octameric organization is widely conserved in the crystal structures of other IMPDHs. We also demonstrated that human IMPDH1 adopts two types of complementary octamers that can pile up into isolated fibers in the presence of MgATP. The aggregation of such fibers in the autosomal dominant mutant, D226N, could explain the onset of the retinopathy adRP10. Thus, the regulatory CBS modules in IMPDHs are functional and they can either modulate catalysis or macromolecular assembly.