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TitleDynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 3248, Year 2024
Publish dateApr 15, 2024
AuthorsLinnea K M Blomgren / Melanie Huber / Sabrina R Mackinnon / Céline Bürer / Arnaud Baslé / Wyatt W Yue / D Sean Froese / Thomas J McCorvie /
PubMed Abstract5,10-methylenetetrahydrofolate reductase (MTHFR) commits folate-derived one-carbon units to generate the methyl-donor S-adenosyl-L-methionine (SAM). Eukaryotic MTHFR appends to the well-conserved ...5,10-methylenetetrahydrofolate reductase (MTHFR) commits folate-derived one-carbon units to generate the methyl-donor S-adenosyl-L-methionine (SAM). Eukaryotic MTHFR appends to the well-conserved catalytic domain (CD) a unique regulatory domain (RD) that confers feedback inhibition by SAM. Here we determine the cryo-electron microscopy structures of human MTHFR bound to SAM and its demethylated product S-adenosyl-L-homocysteine (SAH). In the active state, with the RD bound to a single SAH, the CD is flexible and exposes its active site for catalysis. However, in the inhibited state the RD pocket is remodelled, exposing a second SAM-binding site that was previously occluded. Dual-SAM bound MTHFR demonstrates a substantially rearranged inter-domain linker that reorients the CD, inserts a loop into the active site, positions Tyr404 to bind the cofactor FAD, and blocks substrate access. Our data therefore explain the long-distance regulatory mechanism of MTHFR inhibition, underpinned by the transition between dual-SAM and single-SAH binding in response to cellular methylation status.
External linksNat Commun / PubMed:38622112 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.14 Å
Structure data

18298

8qa4

EMDB-18298, PDB-8qa4:
MTHFR + SAH symmetric dis-inhibited state
Method: EM (single particle) / Resolution: 2.8 Å

18299

8qa5

EMDB-18299, PDB-8qa5:
MTHFR + SAH asymmetric dis-inhibited state
Method: EM (single particle) / Resolution: 3.14 Å

18300

8qa6

EMDB-18300, PDB-8qa6:
MTHFR + SAM inhibited state
Method: EM (single particle) / Resolution: 2.91 Å

Chemicals

ChemComp-SAH:
S-ADENOSYL-L-HOMOCYSTEINE

ChemComp-HOH:
WATER

ChemComp-FAD:
FLAVIN-ADENINE DINUCLEOTIDE / FAD*YM

ChemComp-SAM:
S-ADENOSYLMETHIONINE

Source
  • homo sapiens (human)
KeywordsFLAVOPROTEIN / Dis-inhibited / allosteric / folate / S-adenosylhomocysteine / Inhibited / S-Adenosylmethionin

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