Structure of putative tumor suppressor ALDH1L1.

Commun Biol

Nutrition Research Institute, University of North Carolina at Chapel Hill, 500 Laureate Way, Kannapolis, NC, 28081, USA.

Published: January 2022

AI Article Synopsis

  • The protein ALDH1L1 acts as a putative tumor suppressor by regulating folate metabolism, specifically converting 10-formyltetrahydrofolate into tetrahydrofolate and carbon monoxide (CO).
  • The cryo-EM structures of this enzyme reveal a tetrameric architecture where distinct functional domains interact, emphasizing the importance of N-terminal domains and C-terminal aldehyde dehydrogenase domains in the catalytic process.
  • The study highlights the critical role of the tetrameric form of ALDH1L1 and its intermediate domains, demonstrating how they allow for efficient transfer of the formyl group essential for the enzyme's function.

Article Abstract

Putative tumor suppressor ALDH1L1, the product of natural fusion of three unrelated genes, regulates folate metabolism by catalyzing NADP-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO. Cryo-EM structures of tetrameric rat ALDH1L1 revealed the architecture and functional domain interactions of this complex enzyme. Highly mobile N-terminal domains, which remove formyl from 10-formyltetrahydrofolate, undergo multiple transient inter-domain interactions. The C-terminal aldehyde dehydrogenase domains, which convert formyl to CO, form unusually large interfaces with the intermediate domains, homologs of acyl/peptidyl carrier proteins (A/PCPs), which transfer the formyl group between the catalytic domains. The 4'-phosphopantetheine arm of the intermediate domain is fully extended and reaches deep into the catalytic pocket of the C-terminal domain. Remarkably, the tetrameric state of ALDH1L1 is indispensable for catalysis because the intermediate domain transfers formyl between the catalytic domains of different protomers. These findings emphasize the versatility of A/PCPs in complex, highly dynamic enzymatic systems.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748788PMC
http://dx.doi.org/10.1038/s42003-021-02963-9DOI Listing

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