Reconstituted IMPDH polymers accommodate both catalytically active and inactive conformations

• DOI: 10.1091/mbc.e17-04-0263
• Publication Date: 2017-08-10T00:40:28Z
• Authors: Sajitha A. Anthony; Anika L. Burrell; Matthew C. Johnson; Krisna C. Duong-Ly; Yin-Ming Kuo; Jacqueline C. Sim...; Peter Michener; Andrew Andrews; Justin M. Kollman; Jeffrey R. Peterson
• Keywords: 0301 basic medicine; 03 medical and health sciences; Brief Reports

Several metabolic enzymes undergo reversible polymerization into macromolecular assemblies. The function of these assemblies is often unclear but in some cases they regulate enzyme activity and homeostasis. guanine nucleotide biosynthetic inosine monophosphate dehydrogenase (IMPDH) forms octamers that polymerize helical chains. In mammalian cells, IMPDH filaments can associate micron-length Polymerization are regulated part by binding purine nucleotides to an allosteric regulatory domain. ATP promotes octamer polymerization, whereas GTP a compact, inactive conformation whose ability unknown. Also whether directly alters catalytic activity. To address this, we identified point mutants human IMPDH2 either prevent or promote polymerization. Unexpectedly, found polymerized non-assembled recombinant have comparable activity, substrate affinity, sensitivity validated this finding cells. Electron microscopy revealed substrates shift the equilibrium between active conformations both filament. Unlike other filaments, which selectively stabilize conformations, accommodate multiple states. These conformational states finely tuned availability balance, while may allow cooperative transitions