Figure 6. Model of IMPDH2 assembly and filaments’ role in guanine nucleotide regulation.

(A) Filament assemble when octamer interactions are stabilized by ATP binding to the regulatory domain (pink), and the N-terminal residues (blue) are released by flattening of the catalytic tetramer (green). Filament assembly interactions stabilize the flat conformation. (B) GTP binding stabilizes an inhibited, compressed conformation. Filament is less sensitive to GTP-induced compression, maintaining a population of octamers in mixed activity states. Filaments in the fully compressed GTP-bound state are strained, which promotes disassembly that is inhibited by substrate IMP binding. (C) The equilibrium in (B) explains the different cellular conditions in which IMPDH polymerization occurs. (i) Under homeostatic conditions IMPDH2 is dispersed and activity is regulated by GTP binding to octamers, which balances low levels of de novo synthesis between adenine and guanine pathways. ii) When guanine nucleotides are depleted the equilibrium shifts toward filaments. iii) Proliferative signaling can directly shift the equilibrium toward filaments, where higher flux is maintained through the guanine pathway under elevated GTP concentrations due to reduced sensitivity of the filaments to GTP inhibition (dashed line).