title: MgATP regulates allostery and fiber formation in IMPDHs.
abstract: 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.
authors: CNRS, UMR5048, Universités Montpellier 1 et 2; Centre de Biochimie Structurale, 29 rue de Navacelles, F-34090 Montpellier, France.
authors: Gilles
authors: G
authors: Labesse
authors: Thomas
authors: T
authors: Alexandre
authors: Laurène
authors: L
authors: Vaupré
authors: Isabelle
authors: I
authors: Salard-Arnaud
authors: Joséphine Lai Kee
authors: JL
authors: Him
authors: Bertrand
authors: B
authors: Raynal
authors: Patrick
authors: P
authors: Bron
authors: Hélène
authors: H
authors: Munier-Lehmann
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000494:Allosteric Regulation; D001665:Binding Sites; D001704:Biopolymers / Q000378:metabolism; D018360:Crystallography, X-Ray; D007168:IMP Dehydrogenase / Q000378:metabolism*; D008854:Microscopy, Electron; D008958:Models, Molecular; D011487:Protein Conformation; D011550:Pseudomonas aeruginosa / Q000201:enzymology; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D001704:Biopolymers; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate; D007168:IMP Dehydrogenase