Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation
Matthew C Johnson1, Justin M Kollman1
1Department of Biochemistry, University of Washington, Seattle, United States.
Elife
|January 31, 2020
Summary
Inosine monophosphate dehydrogenase (IMPDH) filaments regulate guanine nucleotide synthesis. IMPDH2 self-assembly alters enzyme activity, enhancing cellular proliferation and immune responses by tuning feedback inhibition.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Inosine monophosphate dehydrogenase (IMPDH) is crucial for guanine nucleotide biosynthesis, impacting cell proliferation and immunity.
- IMPDH undergoes reversible polymerization in response to metabolic needs, but its regulatory role remains unclear.
Purpose of the Study:
- To elucidate the structural basis of IMPDH filament assembly and its regulatory mechanism.
- To understand how IMPDH self-assembly influences enzyme activity and cellular function.
Main Methods:
- Human IMPDH2 structures were determined using cryo-electron microscopy (cryo-EM).
- Analysis of active and inactive enzyme conformations.
- Investigation of allosteric regulation in filament formation.
Main Results:
- Cryo-EM structures revealed the mechanism of human IMPDH2 filament assembly.
- Filament formation alters allosteric regulation, reducing sensitivity to feedback inhibition.
- This mechanism supports guanine nucleotide pool expansion under physiological conditions.
Conclusions:
- IMPDH self-assembly is a key regulatory mechanism modulating enzyme activity.
- Filament-dependent allosteric regulation distinguishes IMPDH from other metabolic enzymes.
- Enzyme self-assembly offers diverse regulatory strategies for metabolic pathways.
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