7rff

Publication Abstract from PubMed

Inosine-5'-monophosphate dehydrogenase (IMPDH), a key regulatory enzyme in purine nucleotide biosynthesis, dynamically assembles filaments in response to changes in metabolic demand. Humans have two isoforms: IMPDH2 filaments reduce sensitivity to feedback inhibition, while IMPDH1 assembly remains uncharacterized. IMPDH1 plays a unique role in retinal metabolism, and point mutants cause blindness. Here, in a series of cryogenic-electron microscopy structures we show that human IMPDH1 assembles polymorphic filaments with different assembly interfaces in extended and compressed states. Retina-specific splice variants introduce structural elements that reduce sensitivity to GTP inhibition, including stabilization of the extended filament form. Finally, we show that IMPDH1 disease mutations fall into two classes: one disrupts GTP regulation and the other has no effect on GTP regulation or filament assembly. These findings provide a foundation for understanding the role of IMPDH1 in retinal function and disease and demonstrate the diverse mechanisms by which metabolic enzyme filaments are allosterically regulated.

IMPDH1 retinal variants control filament architecture to tune allosteric regulation.,Burrell AL, Nie C, Said M, Simonet JC, Fernandez-Justel D, Johnson MC, Quispe J, Buey RM, Peterson JR, Kollman JM Nat Struct Mol Biol. 2022 Jan;29(1):47-58. doi: 10.1038/s41594-021-00706-2. Epub , 2022 Jan 10. PMID:35013599^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.