7p8p

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of Fhit covalently bound to a nucleotide

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:	, ,
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.^[1] 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.^[2]

Function

FHIT_HUMAN Cleaves A-5'-PPP-5'A to yield AMP and ADP. Possible tumor suppressor for specific tissues.^[3]

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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Pekarsky Y, Garrison PN, Palamarchuk A, Zanesi N, Aqeilan RI, Huebner K, Barnes LD, Croce CM. Fhit is a physiological target of the protein kinase Src. Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3775-9. Epub 2004 Mar 8. PMID:15007172 doi:10.1073/pnas.0400481101
↑ Pekarsky Y, Garrison PN, Palamarchuk A, Zanesi N, Aqeilan RI, Huebner K, Barnes LD, Croce CM. Fhit is a physiological target of the protein kinase Src. Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3775-9. Epub 2004 Mar 8. PMID:15007172 doi:10.1073/pnas.0400481101
↑ Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M, Huebner K. Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5"'-P1,P3-triphosphate hydrolase. Biochemistry. 1996 Sep 10;35(36):11529-35. PMID:8794732 doi:10.1021/bi961415t
↑ Herzog D, Jansen J, Mißun M, Diederichs K, Stengel F, Marx A. Chemical Proteomics of the Tumor Suppressor Fhit Covalently Bound to the Cofactor Ap(3)A Elucidates Its Inhibitory Action on Translation. J Am Chem Soc. 2022 May 18;144(19):8613-8623. PMID:35522782 doi:10.1021/jacs.2c00815

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7p8p"

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[7p8p]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7P8P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P8P FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.34&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6BI:[(2~{R},3~{S},4~{R},5~{R})-5-[6-(ethylamino)purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl+dihydrogen+phosphate'>6BI</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6BI:[(2~{R},3~{S},4~{R},5~{R})-5-[6-[6-(2-chloranylethanoylamino)hexylamino]purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl+dihydrogen+phosphate'>6BI</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7p8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p8p OCA], [https://pdbe.org/7p8p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p8p RCSB], [https://www.ebi.ac.uk/pdbsum/7p8p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p8p ProSAT]</span></td></tr>
 </table>

7p8p

From Proteopedia

Current revision

Crystal structure of Fhit covalently bound to a nucleotide

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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