Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Molecular Analysis of the Interaction between Human PTPN21 and the Oncoprotein E7 from Human Papillomavirus Genotype 18

  • Lee, Hye Seon (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Min Wook (Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Jin, Kyeong Sik (Pohang Accelerator Laboratory, Pohang University of Science and Technology) ;
  • Shin, Ho-Chul (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Won Kon (Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Lee, Sang Chul (Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Seung Jun (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Lee, Eun-Woo (Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Ku, Bonsu (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology)
  • Received : 2020.08.14
  • Accepted : 2020.12.08
  • Published : 2021.01.31
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Abstract

Human papillomaviruses (HPVs) cause cellular hyperproliferation-associated abnormalities including cervical cancer. The HPV genome encodes two major viral oncoproteins, E6 and E7, which recruit various host proteins by direct interaction for proteasomal degradation. Recently, we reported the structure of HPV18 E7 conserved region 3 (CR3) bound to the protein tyrosine phosphatase (PTP) domain of PTPN14, a well-defined tumor suppressor, and found that this intermolecular interaction plays a key role in E7-driven transformation and tumorigenesis. In this study, we carried out a molecular analysis of the interaction between CR3 of HPV18 E7 and the PTP domain of PTPN21, a PTP protein that shares high sequence homology with PTPN14 but is putatively oncogenic rather than tumor-suppressive. Through the combined use of biochemical tools, we verified that HPV18 E7 and PTPN21 form a 2:2 complex, with a dissociation constant of 5 nM and a nearly identical binding manner with the HPV18 E7 and PTPN14 complex. Nevertheless, despite the structural similarities, the biological consequences of the E7 interaction were found to differ between the two PTP proteins. Unlike PTPN14, PTPN21 did not appear to be subjected to proteasomal degradation in HPV18-positive HeLa cervical cancer cells. Moreover, knockdown of PTPN21 led to retardation of the migration/invasion of HeLa cells and HPV18 E7-expressing HaCaT keratinocytes, which reflects its protumor activity. In conclusion, the associations of the viral oncoprotein E7 with PTPN14 and PTPN21 are similar at the molecular level but play different physiological roles.

Keywords

Acknowledgement

SAXS measurements were performed at the beamline 4C at the Pohang Accelerator Laboratory in Korea. We appreciate Dr. Eunha Hwang (Korea Basic Science Institute, Korea) for help with the SEC-MALS measurements and Dr. Jungwon Hwang and Dr. Myung Hee Kim (Korea Research Institute of Bioscience and Biotechnology, Korea) for help with the ITC measurements. This study was supported by the National Research Foundation of Korea (NRF_2020R1C1C1008451 and NRF_2019M3E5D6063955 to B.K., NRF_2017M3A9G5083321 to S.C.L., and NRF_2019R1C1C1002831 to E.W.L.) and the KRIBB Research Initiative Programs (to B.K.), which were funded by the Ministry of Science and ICT (MSIT) of Republic of Korea.

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