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IMPDH1 retinal variants control filament architecture to tune allosteric regulation.

Burrell AL, Nie C, Said M, Simonet JC, Fernández-Justel D, Johnson MC, Quispe J, Buey RM, Peterson JR, Kollman JM
Nat Struct Mol Biol 29 47-58 (2022)
Related entries: 7res, 7rfe, 7rff, 7rfg, 7rfh, 7rfi, 7rgd, 7rgi, 7rgl, 7rgm, 7rgq

Cited: 19 times
EuropePMC logo PMID: 35013599

Abstract

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.

Articles - 7rer mentioned but not cited (1)

  1. IMPDH1 retinal variants control filament architecture to tune allosteric regulation. Burrell AL, Nie C, Said M, Simonet JC, Fernández-Justel D, Johnson MC, Quispe J, Buey RM, Peterson JR, Kollman JM. Nat Struct Mol Biol 29 47-58 (2022)


Reviews citing this publication (6)

  1. IMPDH dysregulation in disease: a mini review. Burrell AL, Kollman JM. Biochem Soc Trans 50 71-82 (2022)
  2. Greater than the sum of parts: Mechanisms of metabolic regulation by enzyme filaments. Hvorecny KL, Kollman JM. Curr Opin Struct Biol 79 102530 (2023)
  3. The gateway to guanine nucleotides: Allosteric regulation of IMP dehydrogenases. Buey RM, Fernández-Justel D, Jiménez A, Revuelta JL. Protein Sci 31 e4399 (2022)
  4. Inborn Errors of Purine Salvage and Catabolism. Camici M, Garcia-Gil M, Allegrini S, Pesi R, Bernardini G, Micheli V, Tozzi MG. Metabolites 13 787 (2023)
  5. A journey into the regulatory secrets of the de novo purine nucleotide biosynthesis. Ayoub N, Gedeon A, Munier-Lehmann H. Front Pharmacol 15 1329011 (2024)
  6. Agglomeration: when folded proteins clump together. Romero-Romero ML, Garcia-Seisdedos H. Biophys Rev 15 1987-2003 (2023)

Articles citing this publication (12)



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