6FL5

Structure of human SHMT1-H135N-R137A-E168N mutant at 3.6 Ang. resolution

Summary for 6FL5

• Entry DOI: 10.2210/pdb6fl5/pdb
• Descriptor: Serine hydroxymethyltransferase, cytosolic, PYRIDOXAL-5'-PHOSPHATE, CHLORIDE ION (3 entities in total)
• Functional Keywords: transferase, serine hydroxymethyltransferase, interface, tetramer, ocm, serine, thf, glicine, tca
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 207913.57

Authors

Giardina, G.,Cutruzzola, F.,Lucchi, R. (deposition date: 2018-01-25, release date: 2018-10-10, Last modification date: 2024-01-17)

Primary citation

Giardina, G.,Paone, A.,Tramonti, A.,Lucchi, R.,Marani, M.,Magnifico, M.C.,Bouzidi, A.,Pontecorvi, V.,Guiducci, G.,Zamparelli, C.,Rinaldo, S.,Paiardini, A.,Contestabile, R.,Cutruzzola, F.
The catalytic activity of serine hydroxymethyltransferase is essential for de novo nuclear dTMP synthesis in lung cancer cells.
FEBS J., 285:3238-3253, 2018

PubMed Abstract: Cancer cells reprogramme one-carbon metabolism (OCM) to sustain growth and proliferation. Depending on cell demands, serine hydroxymethyltransferase (SHMT) dynamically changes the fluxes of OCM by reversibly converting serine and tetrahydrofolate (THF) into 5,10-methylene-THF and glycine. SHMT is a tetrameric enzyme that mainly exists in three isoforms; two localize in the cytosol (SHMT1/SHMT2α) and one (SHMT2) in the mitochondria. Both the cytosolic isoforms can also translocate to the nucleus to sustain de novo thymidylate synthesis and support cell proliferation. Finally, the expression levels of the different isoforms are regulated to a certain extent by a yet unknown crosstalk mechanism. We have designed and fully characterized a set of three SHMT1 mutants, which uncouple the oligomeric state of the enzyme from its catalytic activity. We have then investigated the effects of the mutations on SHMT1 nuclear localization, cell viability and crosstalk in lung cancer cells (A549; H1299). Our data reveal that in these cell lines de novo thymidylate synthesis requires SHMT1 to be active, regardless of its oligomeric state. We have also confirmed that the crosstalk between the cytosolic and mitochondrial SHMT actually takes place and regulates the expression of the two isoforms. Apparently, the crosstalk mechanism is independent from the oligomeric state and the catalytic activity of SHMT1.

PubMed: 30035852
DOI: 10.1111/febs.14610

Experimental method

X-RAY DIFFRACTION (3.6 Å)