The role of filament assembly in regulating retinal IMPDH1 splice variants

Inosine-5′-monophosphate dehydrogenase (IMPDH) is a key regulatory enzyme of purine nucleotide biosynthesis that dynamically assembles filaments in response to changes in metabolic demand. Humans have two isoforms, IMDPH1 and IMPDH2, with IMPDH1 playing a unique role in retinal metabolism. Several dominant point mutations in IMPDH1 lead to retinal degeneration. Here, we demonstrate assembly of IMPDH1 into filamentous polymers in the vertebrate retina. Cryo-EM structures show that retina-specific splice variants of IMPDH1 introduce structural elements that reduce sensitivity to feedback inhibition of the enzyme by GTP. We show that disease-associated IMPDH1 mutations fall into two classes: one disrupts GTP regulation and the other has no effect on GTP regulation or filament assembly. Finally, we demonstrate that IMPDH1 filament assembly can itself be regulated by post-translational modifications that tune enzyme activity by disrupting polymerization. Taken together, expression of splice variants and post-translational modifications that influence IMPDH1 filament stability provide additional layers of regulatory control that balance the high retinal demand for purine nucleotides.