6iwd

From Proteopedia

(Difference between revisions)

Current revision

The PTP domain of human PTPN14 in a complex with the CR3 domain of HPV18 E7

Structural highlights

6iwd is a 2 chain structure with sequence from Homo sapiens and Human papillomavirus type 18. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PTN14_HUMAN Lymphedema-posterior choanal atresia syndrome. The disease is caused by mutations affecting the gene represented in this entry. A homozygous deletion in PTPN14 predicted to result in frameshift and premature truncation, has been shown to be the cause of choanal atresia and lymphedema in one family. Influence clinical severity of hereditary haemorragic telagiectasia (HHT).^[1]

Function

PTN14_HUMAN Protein tyrosine phosphatase which may play a role in the regulation of lymphangiogenesis, cell-cell adhesion, cell-matrix adhesion, cell migration, cell growth and also regulates TGF-beta gene expression, thereby modulating epithelial-mesenchymal transition. Mediates beta-catenin dephosphorylation at adhesion junctions. Acts as a negative regulator of the oncogenic property of YAP, a downstream target of the hippo pathway, in a cell density-dependent manner. May function as a tumor suppressor.^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Human papillomaviruses (HPVs) are causative agents of various diseases associated with cellular hyperproliferation, including cervical cancer, one of the most prevalent tumors in women. E7 is one of the two HPV-encoded oncoproteins and directs recruitment and subsequent degradation of tumor-suppressive proteins such as retinoblastoma protein (pRb) via its LxCxE motif. E7 also triggers tumorigenesis in a pRb-independent pathway through its C-terminal domain, which has yet been largely undetermined, with a lack of structural information in a complex form with a host protein. Herein, we present the crystal structure of the E7 C-terminal domain of HPV18 belonging to the high-risk HPV genotypes bound to the catalytic domain of human nonreceptor-type protein tyrosine phosphatase 14 (PTPN14). They interact directly and potently with each other, with a dissociation constant of 18.2 nM. Ensuing structural analysis revealed the molecular basis of the PTPN14-binding specificity of E7 over other protein tyrosine phosphatases and also led to the identification of PTPN21 as a direct interacting partner of E7. Disruption of HPV18 E7 binding to PTPN14 by structure-based mutagenesis impaired E7's ability to promote keratinocyte proliferation and migration. Likewise, E7 binding-defective PTPN14 was resistant for degradation via proteasome, and it was much more effective than wild-type PTPN14 in attenuating the activity of downstream effectors of Hippo signaling and negatively regulating cell proliferation, migration, and invasion when examined in HPV18-positive HeLa cells. These results therefore demonstrated the significance and therapeutic potential of the intermolecular interaction between HPV E7 and host PTPN14 in HPV-mediated cell transformation and tumorigenesis.

Structural basis for recognition of the tumor suppressor protein PTPN14 by the oncoprotein E7 of human papillomavirus.,Yun HY, Kim MW, Lee HS, Kim W, Shin JH, Kim H, Shin HC, Park H, Oh BH, Kim WK, Bae KH, Lee SC, Lee EW, Ku B, Kim SJ PLoS Biol. 2019 Jul 19;17(7):e3000367. doi: 10.1371/journal.pbio.3000367. PMID:31323018^[9]

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

References

↑ Benzinou M, Clermont FF, Letteboer TG, Kim JH, Espejel S, Harradine KA, Arbelaez J, Luu MT, Roy R, Quigley D, Higgins MN, Zaid M, Aouizerat BE, van Amstel JK, Giraud S, Dupuis-Girod S, Lesca G, Plauchu H, Hughes CC, Westermann CJ, Akhurst RJ. Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. Nat Commun. 2012 Jan 10;3:616. doi: 10.1038/ncomms1633. PMID:22233626 doi:http://dx.doi.org/10.1038/ncomms1633
↑ Wadham C, Gamble JR, Vadas MA, Khew-Goodall Y. Translocation of protein tyrosine phosphatase Pez/PTPD2/PTP36 to the nucleus is associated with induction of cell proliferation. J Cell Sci. 2000 Sep;113 ( Pt 17):3117-23. PMID:10934049
↑ Wadham C, Gamble JR, Vadas MA, Khew-Goodall Y. The protein tyrosine phosphatase Pez is a major phosphatase of adherens junctions and dephosphorylates beta-catenin. Mol Biol Cell. 2003 Jun;14(6):2520-9. doi: 10.1091/mbc.e02-09-0577. Epub 2003 Feb, 6. PMID:12808048 doi:http://dx.doi.org/10.1091/mbc.e02-09-0577
↑ Wyatt L, Wadham C, Crocker LA, Lardelli M, Khew-Goodall Y. The protein tyrosine phosphatase Pez regulates TGFbeta, epithelial-mesenchymal transition, and organ development. J Cell Biol. 2007 Sep 24;178(7):1223-35. doi: 10.1083/jcb.200705035. PMID:17893246 doi:http://dx.doi.org/10.1083/jcb.200705035
↑ Au AC, Hernandez PA, Lieber E, Nadroo AM, Shen YM, Kelley KA, Gelb BD, Diaz GA. Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans. Am J Hum Genet. 2010 Sep 10;87(3):436-44. doi: 10.1016/j.ajhg.2010.08.008. PMID:20826270 doi:http://dx.doi.org/10.1016/j.ajhg.2010.08.008
↑ Benzinou M, Clermont FF, Letteboer TG, Kim JH, Espejel S, Harradine KA, Arbelaez J, Luu MT, Roy R, Quigley D, Higgins MN, Zaid M, Aouizerat BE, van Amstel JK, Giraud S, Dupuis-Girod S, Lesca G, Plauchu H, Hughes CC, Westermann CJ, Akhurst RJ. Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. Nat Commun. 2012 Jan 10;3:616. doi: 10.1038/ncomms1633. PMID:22233626 doi:http://dx.doi.org/10.1038/ncomms1633
↑ Liu X, Yang N, Figel SA, Wilson KE, Morrison CD, Gelman IH, Zhang J. PTPN14 interacts with and negatively regulates the oncogenic function of YAP. Oncogene. 2013 Mar 7;32(10):1266-73. doi: 10.1038/onc.2012.147. Epub 2012 Apr 23. PMID:22525271 doi:http://dx.doi.org/10.1038/onc.2012.147
↑ Wang W, Huang J, Wang X, Yuan J, Li X, Feng L, Park JI, Chen J. PTPN14 is required for the density-dependent control of YAP1. Genes Dev. 2012 Sep 1;26(17):1959-71. doi: 10.1101/gad.192955.112. PMID:22948661 doi:http://dx.doi.org/10.1101/gad.192955.112
↑ Yun HY, Kim MW, Lee HS, Kim W, Shin JH, Kim H, Shin HC, Park H, Oh BH, Kim WK, Bae KH, Lee SC, Lee EW, Ku B, Kim SJ. Structural basis for recognition of the tumor suppressor protein PTPN14 by the oncoprotein E7 of human papillomavirus. PLoS Biol. 2019 Jul 19;17(7):e3000367. doi: 10.1371/journal.pbio.3000367. PMID:31323018 doi:http://dx.doi.org/10.1371/journal.pbio.3000367

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6iwd"

@@ Line 3: / Line 3: @@
 <StructureSection load='6iwd' size='340' side='right'caption='[[6iwd]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6iwd]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IWD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6IWD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6iwd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_papillomavirus_type_18 Human papillomavirus type 18]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IWD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6IWD FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6iwd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6iwd OCA], [http://pdbe.org/6iwd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6iwd RCSB], [http://www.ebi.ac.uk/pdbsum/6iwd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6iwd ProSAT]</span></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=6iwd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6iwd OCA], [https://pdbe.org/6iwd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6iwd RCSB], [https://www.ebi.ac.uk/pdbsum/6iwd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6iwd ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/PTN14_HUMAN PTN14_HUMAN]] Lymphedema-posterior choanal atresia syndrome. The disease is caused by mutations affecting the gene represented in this entry. A homozygous deletion in PTPN14 predicted to result in frameshift and premature truncation, has been shown to be the cause of choanal atresia and lymphedema in one family.  Influence clinical severity of hereditary haemorragic telagiectasia (HHT).<ref>PMID:22233626</ref>
+[https://www.uniprot.org/uniprot/PTN14_HUMAN PTN14_HUMAN] Lymphedema-posterior choanal atresia syndrome. The disease is caused by mutations affecting the gene represented in this entry. A homozygous deletion in PTPN14 predicted to result in frameshift and premature truncation, has been shown to be the cause of choanal atresia and lymphedema in one family.  Influence clinical severity of hereditary haemorragic telagiectasia (HHT).<ref>PMID:22233626</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/PTN14_HUMAN PTN14_HUMAN]] Protein tyrosine phosphatase which may play a role in the regulation of lymphangiogenesis, cell-cell adhesion, cell-matrix adhesion, cell migration, cell growth and also regulates TGF-beta gene expression, thereby modulating epithelial-mesenchymal transition. Mediates beta-catenin dephosphorylation at adhesion junctions. Acts as a negative regulator of the oncogenic property of YAP, a downstream target of the hippo pathway, in a cell density-dependent manner. May function as a tumor suppressor.<ref>PMID:10934049</ref> <ref>PMID:12808048</ref> <ref>PMID:17893246</ref> <ref>PMID:20826270</ref> <ref>PMID:22233626</ref> <ref>PMID:22525271</ref> <ref>PMID:22948661</ref>  [[http://www.uniprot.org/uniprot/Q76Z96_HPV18 Q76Z96_HPV18]] E7 protein has both transforming and trans-activating activities.[PIRNR:PIRNR003407]  Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle. Stimulation of progression from G1 to S phase allows the virus to efficiently use the cellular DNA replicating machinery to achieve viral genome replication. E7 protein has both transforming and trans-activating activities. Induces the disassembly of the E2F1 transcription factor from RB1, with subsequent transcriptional activation of E2F1-regulated S-phase genes. Interferes with host histone deacetylation mediated by HDAC1 and HDAC2, leading to transcription activation. Plays also a role in the inhibition of both antiviral and antiproliferative functions of host interferon alpha. Interaction with host TMEM173/STING impairs the ability of TMEM173/STING to sense cytosolic DNA and promote the production of type I interferon (IFN-alpha and IFN-beta).[HAMAP-Rule:MF_04004][SAAS:SAAS00955501]
+[https://www.uniprot.org/uniprot/PTN14_HUMAN PTN14_HUMAN] Protein tyrosine phosphatase which may play a role in the regulation of lymphangiogenesis, cell-cell adhesion, cell-matrix adhesion, cell migration, cell growth and also regulates TGF-beta gene expression, thereby modulating epithelial-mesenchymal transition. Mediates beta-catenin dephosphorylation at adhesion junctions. Acts as a negative regulator of the oncogenic property of YAP, a downstream target of the hippo pathway, in a cell density-dependent manner. May function as a tumor suppressor.<ref>PMID:10934049</ref> <ref>PMID:12808048</ref> <ref>PMID:17893246</ref> <ref>PMID:20826270</ref> <ref>PMID:22233626</ref> <ref>PMID:22525271</ref> <ref>PMID:22948661</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 6iwd" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Human papillomavirus type 18]]
 [[Category: Large Structures]]
-[[Category: Protein-tyrosine-phosphatase]]
+[[Category: Kim SJ]]
-[[Category: Kim, S J]]
+[[Category: Ku B]]
-[[Category: Ku, B]]
+[[Category: Yun H-Y]]
-[[Category: Yun, H Y]]
-[[Category: Oncoprotein]]

6iwd

From Proteopedia

Current revision

The PTP domain of human PTPN14 in a complex with the CR3 domain of HPV18 E7

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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