IMPDH1 retinal variants control filament architecture to tune allosteric regulation

Burrell, Anika; Nie, Chuankai; Said, Meerit; Simonet, Jacqueline C.; Fernandez-Justel, D.; Johnson, Matthew C.; Quispe, Joel; Buey, Rubén M.; Peterson, Jeffrey R.; Kollman, Justin M.

doi:10.1038/s41594-021-00706-2

Cited by 34 publications

(101 citation statements)

References 67 publications

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“…The IMPDH enzymatic reaction is well characterized [1]. In cells, IMPDH assembles into large filamentous ultrastructures, and recent in vitro work has defined the mechanism of IMPDH self-assembly into filaments, and shown that assembly plays a role in allosteric regulation [2][3][4][5][6]. In humans, there are two isoforms of IMPDH that share 84% sequence identity: IMPDH2 is up-regulated in proliferating cells while IMPDH1 plays a housekeeping role and is expressed in most tissues [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…Thorough characterization of IMPDH filaments in vitro has revealed that nucleotide binding to the regulatory domain promotes self-assembly of filaments made of stacked octamers ( Figure 1E ) [ 3 , 4 , 46 ]. IMPDH2 filaments serve a regulatory function, allowing the protein to resist GTP-feedback inhibition [ 5 ] while canonical IMPDH1 filaments have no effect on activity or inhibition [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The two IMPDH isoforms have different compressed filament architectures [ 5 , 6 ]. ATP binding in sites 1 and 2 in the regulatory domain, drives assembly of active IMPDH filaments in the extended octamer state that are identical for IMPDH1 and IMPDH2 ( Figure 2A , B ) [ 5 , 6 ]. GTP binding at regulatory domain sites 2 and 3 induces two conformation changes: compression of the octamer and flexing of the catalytic domain to an active ‘flat’ or partially inactive ‘bowed’ conformation.…”

Section: Introductionmentioning

confidence: 99%

“…Summary of the conditions IMPDH1 disease mutations have been tested. Dashed line indicates there are no published results, bold text indicates a finding that is indistinguishable from wildtype, N stands for 'normal', while italic text indicates a behavior different from wildtype; 1 Ref [6]…”

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confidence: 99%

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IMPDH dysregulation in disease: a mini review

Burrell

2022

Biochemical Society Transactions

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Inosine-5′-monophosphate dehydrogenase (IMPDH) is a highly conserved enzyme in purine metabolism that is tightly regulated on multiple levels. IMPDH has a critical role in purine biosynthesis, where it regulates flux at the branch point between adenine and guanine nucleotide synthesis, but it also has a role in transcription regulation and other moonlighting functions have been described. Vertebrates have two isoforms, IMPDH1 and IMPDH2, and point mutations in each are linked to human disease. Mutations in IMPDH2 in humans are associated with neurodevelopmental disease, but the effects of mutations at the enzyme level have not yet been characterized. Mutations in IMPDH1 lead to retinal degeneration in humans, and recent studies have characterized how they cause functional defects in regulation. IMPDH1 is expressed as two unique splice variants in the retina, a tissue with very high and specific demands for purine nucleotides. Recent studies have revealed functional differences among splice variants, demonstrating that retinal variants up-regulate guanine nucleotide synthesis by reducing sensitivity to feedback inhibition by downstream products. A better understanding of the role of IMPDH1 in the retina and the characterization of an animal disease model will be critical for determining the molecular mechanism of IMPDH1-associated blindness.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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IMPDH dysregulation in disease: a mini review

Burrell

2022

Biochemical Society Transactions

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Asymmetric inheritance of cytoophidia could contribute to determine cell fate and plasticity

Darekar

Laı́n

2022

BioEssays

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Two enzymes involved in the synthesis of pyrimidine and purine nucleotides, CTP synthase (CTPS) and IMP dehydrogenase (IMPDH), can assemble into a single or very few large filaments called rods and rings (RR) or cytoophidia. Most recently, asymmetric cytoplasmic distribution of organelles during cell division has been described as a decisive event in hematopoietic stem cell fate. We propose that cytoophidia, which could be considered as membrane-less organelles, may also be distributed asymmetrically during mammalian cell division as previously described for Schizosaccharomyces pombe.Furthermore, because each type of nucleotide intervenes in distinct processes (e.g., membrane synthesis, glycosylation, and G protein-signaling), alterations in the rate of synthesis of specific nucleotide types could influence cell differentiation in multiple ways. Therefore, we hypothesize that whether a daughter cell inherits or not CTPS or IMPDH filaments determines its fate and that this asymmetric inheritance, together with the dynamic nature of these structures enables plasticity in a cell population.

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Biochemical communication between filament‐forming enzymes

Bearne

2024

BioEssays

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A host of metabolic enzymes reversibly self‐assemble to form membrane‐less, intracellular filaments under normal physiological conditions and in response to stress. Often, these enzymes reside at metabolic control points, suggesting that filament formation affords an additional regulatory mechanism. Examples include cytidine‐5′‐triphosphate (CTP) synthase (CTPS), which catalyzes the rate‐limiting step for the de novo biosynthesis of CTP; inosine‐5′‐monophosphate dehydrogenase (IMPDH), which controls biosynthetic access to guanosine‐5′‐triphosphate (GTP); and ∆1‐pyrroline‐5‐carboxylate (P5C) synthase (P5CS) that catalyzes the formation of P5C, which links the Krebs cycle, urea cycle, and proline metabolism. Intriguingly, CTPS can exist in co‐assemblies with IMPDH or P5CS. Since GTP is an allosteric activator of CTPS, the association of CTPS and IMPDH filaments accords with the need to coordinate pyrimidine and purine biosynthesis. Herein, a hypothesis is presented furnishing a biochemical connection underlying co‐assembly of CTPS and P5CS filaments – potent inhibition of CTPS by glutamate γ‐semialdehyde, the open‐chain form of P5C.

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IMPDH1 retinal variants control filament architecture to tune allosteric regulation

Cited by 34 publications

References 67 publications

IMPDH dysregulation in disease: a mini review

IMPDH dysregulation in disease: a mini review

Asymmetric inheritance of cytoophidia could contribute to determine cell fate and plasticity

Biochemical communication between filament‐forming enzymes

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