IMPDH1 retinal variants control filament architecture to tune allosteric regulation

  • Nat Struct Mol Biol. 2022 Jan;29(1):47-58. doi: 10.1038/s41594-021-00706-2.
Anika L Burrell  1 ,  Chuankai Nie  1  2 ,  Meerit Said  1 ,  Jacqueline C Simonet  3  4 ,  David Fernández-Justel  5 ,  Matthew C Johnson  1  6 ,  Joel Quispe  1 ,  Rubén M Buey  5 ,  Jeffrey R Peterson  3 ,  Justin M Kollman  7
Affiliations
  • 1. Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • 2. Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.
  • 3. Cancer Epigenetics and Signaling Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • 4. Department of Biology, Arcadia University, Glenside, PA, USA.
  • 5. Metabolic Engineering Group, Departamento de Microbiología y Genética, Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.
  • 6. Department of Structural Biology, Genentech, South San Francisco, CA, USA.
  • 7. Department of Biochemistry, University of Washington, Seattle, WA, USA. [email protected].
PMID: 35013599 DOI: 10.1038/s41594-021-00706-2
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.