IMPDH1 retinal variants control filament architecture to tune allosteric regulation

[EN]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...

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Detalles Bibliográficos
Autores: Burrell, Anika L, Nie, Chuankai, Said, Meerit, Simonet, Jacqueline C, Fernández Justel, David, Johnson, Matthew C, Quispe, Joel, Martínez Buey, Rubén, Peterson, Jeffrey R, Kollman, Justin M, Burrell, Anika L., Simonet, Jacqueline C., Johnson, Matthew C., Buey, Rubén M., Peterson, Jeffrey R., Kollman, Justin M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Salamanca (USAL)
Repositorio:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/168989
Acceso en línea:http://hdl.handle.net/10366/168989
Access Level:acceso abierto
Palabra clave:IMP dehydrogenase
retina
Nucleotide metabolism
Allosteric regulation
Guanosine Triphosphate
Allosteric Regulation
Retinal Diseases
IMP Dehydrogenase
regulación alostérica
guanosina trifosfato
IMP deshidrogenasa
enfermedades de la retina
Descripción
Sumario:[EN]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.

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