7p8p

Crystal structure of Fhit covalently bound to a nucleotide

spinqualitylabelsall models 7p8p, resolution 2.34Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7p8p is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.34Å Ligands: 6BI, NA, TRS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease FHIT_HUMAN Note=A chromosomal aberration involving FHIT has been found in a lymphoblastoid cell line established from a family with renal cell carcinoma and thyroid carcinoma. Translocation t(3;8)(p14.2;q24.1) with RNF139. Although the 3p14.2 breakpoint has been shown to interrupt FHIT in its 5-prime non-coding region, it is unlikely that FHIT is causally related to renal or other malignancies. Note=Associated with digestive tract cancers. Numerous tumor types are found to have aberrant forms of FHIT protein due to deletions in a coding region of chromosome 3p14.2 including the fragile site locus FRA3B. Function FHIT_HUMAN Cleaves A-5'-PPP-5'A to yield AMP and ADP. Possible tumor suppressor for specific tissues. Publication Abstract from PubMed The tumor suppressor protein fragile histidine triad (Fhit) is known to be associated with genomic instability and apoptosis. The tumor-suppressive function of Fhit depends on the interaction with the alarmone diadenosine triphosphate (Ap(3)A), a noncanonical nucleotide whose concentration increases upon cellular stress. How the Fhit-Ap(3)A complex exerts its signaling function is unknown. Here, guided by a chemical proteomics approach employing a synthetic stable Fhit-Ap(3)A complex, we found that the Fhit-Ap(3)A complex, but not Fhit or Ap(3)A alone, impedes translation. Our findings provide a mechanistic model in which Fhit translocates from the nucleolus into the cytosol upon stress to form an Fhit-Ap(3)A complex. The Fhit-Ap(3)A complex impedes translation both in vitro and in vivo, resulting in reduced cell viability. Overall, our findings provide a mechanistic model by which the tumor suppressor Fhit collaborates with the alarmone Ap(3)A to regulate cellular proliferation. Chemical Proteomics of the Tumor Suppressor Fhit Covalently Bound to the Cofactor Ap(3)A Elucidates Its Inhibitory Action on Translation.,Herzog D, Jansen J, Missun M, Diederichs K, Stengel F, Marx A J Am Chem Soc. 2022 May 18;144(19):8613-8623. doi: 10.1021/jacs.2c00815. Epub , 2022 May 6. PMID:35522782 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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