Journal of Microbiology

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Molecular analysis of the interaction between ubiquitin-specific protease 7 and large T antigen of Merkel cell polyomavirus: Dahwan Lim, Jung-Hwan Park, Ho-Chul Shin, Seung Jun Kim, Bonsu Ku; J. Microbiol. 2026;64(2):e2511009. Published online February 12, 2026; DOI: https://doi.org/10.71150/jm.2511009

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Abstract PDF Supplementary Material: Merkel cell polyomavirus (MCPyV) is the primary causative agent of Merkel cell carcinoma, a rare but highly aggressive neuroendocrine skin cancer. Large T antigen (LT), one of two oncoproteins encoded by MCPyV, sustains the proliferation of MCPyV-infected tumor cells. LT contains multiple protein-binding motifs that mediate interactions with diverse host proteins essential for its function. Among these, ubiquitin-specific protease 7 (Usp7), a deubiquitinase that regulates the stability of multiple substrates, including p53, is a recently identified LT-interacting protein. In the present study, we characterized the intermolecular interaction between Usp7 and MCPyV LT using biochemical analyses and AlphaFold-based structural modeling. Our results demonstrate that MCPyV LT directly interacts with the TRAF domain of Usp7 via a unique binding motif that is distinct from the canonical sequence. Moreover, MCPyV LT attenuates the p53-deubiquitinating activity of Usp7, providing insights into the molecular function of this viral oncoprotein.

Review

Structural analysis of dual specificity phosphatases, the only type of protein tyrosine phosphatases found in humans and across diverse microorganisms: Bonsu Ku; J. Microbiol. 2025;63(10):e2506006. Published online October 31, 2025; DOI: https://doi.org/10.71150/jm.2506006

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Abstract PDF Supplementary Material: Dual specificity phosphatases (DUSPs), a subfamily of the protein tyrosine phosphatase (PTP) family, dephosphorylate not only phosphotyrosine but also phosphoserine and phosphothreonine residues. Beyond the 26 members of this family in humans, DUSPs represent the only type of PTPs found across a wide range of microorganisms, including bacteria, archaea, and viruses. This review presents a comprehensive structural analysis of human and microbial DUSPs. These proteins commonly share core features, such as a typical DUSP fold, shallow active site pocket, signature active site motif known as the P-loop, and conserved aspartate residue that acts as a general acid/base. However, DUSPs from diverse microorganisms also display unique structural and functional characteristics. Pseudomonas aeruginosa TpbA is the only bacterial DUSP identified to date, while a second candidate was proposed in this review. Archaeal DUSPs are hyperthermostable, contain a unique motif in their P-loops, and employ dual general acid/base residues. Poxviral DUSPs are characterized by the formation of domain-swapped homodimers. The presence of DUSPs across all domains of life and viruses, along with their low specificity for phosphorylated amino acids and structural similarity to classical PTPs, suggests that DUSPs represent the ancestral form of PTPs.

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Crystal structures of the μ2 subunit of clathrin-adaptor protein 2 in complex with peptides derived from human papillomavirus 16 E7: Sujin Jung, Dahwan Lim, Joon Sig Choi, Ho-Chul Shin, Seung Jun Kim, Bonsu Ku; J. Microbiol. 2025;63(8):e2505003. Published online August 31, 2025; DOI: https://doi.org/10.71150/jm.2505003

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Abstract PDF: Human papillomaviruses (HPVs) cause abnormal cellular proliferation, leading to malignant or benign lesions, such as cervical cancer and warts. The genome of HPV16, the most prevalent high-risk oncogenic genotype within the Alphapapillomavirus genus, encodes two oncoproteins. One of these proteins, E7, interacts with multiple host proteins and modulates their functions through distinct pathways. The CR2 domain of HPV16 E7 was recently reported to interact with the μ2 subunit of clathrin-adaptor protein 2 (AP2-μ2), an adaptor complex involved in cargo internalization during clathrin-mediated endocytosis. In this study, to provide molecular insights into their intermolecular interactions, we determined the crystal structures of AP2-μ2 in complex with the HPV16 E7-derived peptides. Subsequent biochemical analyses revealed that this interaction is primarily maintained by the Y-x-x-Φ motif and further supported by acidic cluster residues of HPV16 E7. Finally, sequence alignment of the E7 CR2 domains from various HPV genotypes showed that the AP2-μ2-binding motif is largely conserved in Alpha-, Beta-, and Mupapillomaviruses, but not in Nu- and Gammapapillomaviruses.

Journal Articles

Crystal Structures of Plk1 Polo‑Box Domain Bound to the Human Papillomavirus Minor Capsid Protein L2‑Derived Peptide: Sujin Jung , Hye Seon Lee , Ho-Chul Shin , Joon Sig Choi , Seung Jun Kim , Bonsu Ku; J. Microbiol. 2023;61(8):755-764. Published online September 8, 2023; DOI: https://doi.org/10.1007/s12275-023-00071-3

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Abstract PDF

Human papillomaviruses (HPVs) can increase the proliferation of infected cells during HPV-driven abnormalities, such as cervical cancer or benign warts. To date, more than 200 HPV genotypes have been identified, most of which are classified into three major genera: Alphapapillomavirus, Betapapillomavirus, and Gammapapillomavirus. HPV genomes commonly encode two structural (L1 and L2) and seven functional (E1, E2, E4–E7, and E8) proteins. L2, the minor structural protein of HPVs, not only serves as a viral capsid component but also interacts with various human proteins during viral infection. A recent report revealed that L2 of HPV16 recruits polo-like kinase 1 (Plk1), a master regulator of eukaryotic mitosis and cell cycle progression, for the delivery of viral DNA to mitotic chromatin during HPV16 infection. In this study, we verified the direct and potent interactions between the polo-box domain (PBD) of Plk1 and PBD-binding motif (S–S–pT–P)-containing phosphopeptides derived from L2 of HPV16/HPV18 (high-risk alphapapillomaviruses), HPV5b (low-risk betapapillomavirus), and HPV4 (low-risk gammapapillomavirus). Subsequent structural determination of the Plk1 PBD bound to the HPV18 or HPV4 L2-derived phosphopeptide demonstrated that they interact with each other in a canonical manner, in which electrostatic interactions and hydrogen bonds play key roles in sustaining the complex. Therefore, our structural and biochemical data imply that Plk1 is a broad binding target of L2 of various HPV genotypes belonging to the Alpha-, Beta-, and Gammapapillomavirus genera.

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Crystal structures of the μ2 subunit of clathrin-adaptor protein 2 in complex with peptides derived from human papillomavirus 16 E7
Sujin Jung, Dahwan Lim, Joon Sig Choi, Ho-Chul Shin, Seung Jun Kim, Bonsu Ku
Journal of Microbiology.2025; 63(8): e2505003. CrossRef

Structural and biochemical analysis of the PTPN4 PDZ domain bound to the C-terminal tail of the human papillomavirus E6 oncoprotein: Hye Seon Lee , Hye-Yeoung Yun , Eun-Woo Lee , Ho-Chul Shin , Seung Jun Kim , Bonsu Ku; J. Microbiol. 2022;60(4):395-401. Published online January 28, 2022; DOI: https://doi.org/10.1007/s12275-022-1606-1

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Abstract PDF

High-risk genotypes of human papillomaviruses (HPVs) are directly implicated in various abnormalities associated with cellular hyperproliferation, including cervical cancer. E6 is one of two oncoproteins encoded in the HPV genome, which recruits diverse PSD-95/Dlg/ZO-1 (PDZ) domain-containing human proteins through its C-terminal PDZ-binding motif (PBM) to be degraded by means of the proteasome pathway. Among the three PDZ domain-containing protein tyrosine phosphatases, protein tyrosine phosphatase non-receptor type 3 (PTPN3) and PTPN13 were identified to be recognized by HPV E6 in a PBM-dependent manner. However, whether HPV E6 associates with PTPN4, which also has a PDZ domain and functions as an apoptosis regulator, remains undetermined. Herein, we present structural and biochemical evidence demonstrating the direct interaction between the PBM of HPV16 E6 and the PDZ domain of human PTPN4 for the first time. X-ray crystallographic structure determination and binding measurements using isothermal titration calorimetry demonstrated that hydrophobic interactions in which Leu158 of HPV16 E6 plays a key role and a network of intermolecular hydrogen bonds sustain the complex formation between PTPN4 PDZ and the PBM of HPV16 E6. In addition, it was verified that the corresponding motifs from several other highrisk HPV genotypes, including HPV18, HPV31, HPV33, and HPV45, bind to PTPN4 PDZ with comparable affinities, suggesting that PTPN4 is a common target of various pathogenic HPV genotypes.

Citations

Citations to this article as recorded by

De-regulation of aurora kinases by oncogenic HPV; implications in cancer development and treatment
Kemi Hannah Oladipo, Joanna L. Parish
Tumour Virus Research.2025; 19: 200314. CrossRef
Crystal structures of the μ2 subunit of clathrin-adaptor protein 2 in complex with peptides derived from human papillomavirus 16 E7
Sujin Jung, Dahwan Lim, Joon Sig Choi, Ho-Chul Shin, Seung Jun Kim, Bonsu Ku
Journal of Microbiology.2025; 63(8): e2505003. CrossRef
Bioinformatics Analysis of Human Papillomavirus 16 Integration in Cervical Cancer: Changes in MAGI-1 Expression in Premalignant Lesions and Invasive Carcinoma
Oscar Catalán-Castorena, Olga Lilia Garibay-Cerdenares, Berenice Illades-Aguiar, Rocio Castillo-Sánchez, Ma. Isabel Zubillaga-Guerrero, Marco Antonio Leyva-Vazquez, Sergio Encarnacion-Guevara, Eugenia Flores-Alfaro, Mónica Ramirez-Ruano, Luz del Carmen Al
Cancers.2024; 16(12): 2225. CrossRef
Comparative structural studies on Bovine papillomavirus E6 oncoproteins: Novel insights into viral infection and cell transformation from homology modeling and molecular dynamics simulations
Lucas Alexandre Barbosa de Oliveira Santos, Tales de Albuquerque Leite Feitosa, Marcus Vinicius de Aragão Batista
Genetics and Molecular Biology.2024;[Epub] CrossRef
Crystal Structures of Plk1 Polo-Box Domain Bound to the Human Papillomavirus Minor Capsid Protein L2-Derived Peptide
Sujin Jung, Hye Seon Lee, Ho-Chul Shin, Joon Sig Choi, Seung Jun Kim, Bonsu Ku
Journal of Microbiology.2023; 61(8): 755. CrossRef
The effects of HPV oncoproteins on host communication networks: Therapeutic connotations
Josipa Skelin, Ho Yin Luk, Dražan Butorac, Siaw Shi Boon, Vjekoslav Tomaić
Journal of Medical Virology.2023;[Epub] CrossRef
Structural analysis of human papillomavirus E6 interactions with Scribble PDZ domains
Bryce Z. Stewart, Sofia Caria, Patrick O. Humbert, Marc Kvansakul
The FEBS Journal.2023; 290(11): 2868. CrossRef
Viral manipulation of cell polarity signalling
Airah Javorsky, Patrick O. Humbert, Marc Kvansakul
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.2023; 1870(7): 119536. CrossRef
Mechanistic role of HPV-associated early proteins in cervical cancer: Molecular pathways and targeted therapeutic strategies
Rahul Bhattacharjee, Sabya Sachi Das, Smruti Sudha Biswal, Arijit Nath, Debangshi Das, Asmita Basu, Sumira Malik, Lamha Kumar, Sulagna Kar, Sandeep Kumar Singh, Vijay Jagdish Upadhye, Danish Iqbal, Suliman Almojam, Shubhadeep Roychoudhury, Shreesh Ojha, J
Critical Reviews in Oncology/Hematology.2022; 174: 103675. CrossRef

Crystal structure of human LC8 bound to a peptide from Ebola virus VP35: Dahwan Lim , Ho-Chul Shin , Joon Sig Choi , Seung Jun Kim , Bonsu Ku; J. Microbiol. 2021;59(4):410-416. Published online February 25, 2021; DOI: https://doi.org/10.1007/s12275-021-0641-7

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Abstract PDF

Zaire ebolavirus, commonly called Ebola virus (EBOV), is an RNA virus that causes severe hemorrhagic fever with high mortality. Viral protein 35 (VP35) is a virulence factor encoded in the EBOV genome. VP35 inhibits host innate immune responses and functions as a critical cofactor for viral RNA replication. EBOV VP35 contains a short conserved motif that interacts with dynein light chain 8 (LC8), which serves as a regulatory hub protein by associating with various LC8-binding proteins. Herein, we present the crystal structure of human LC8 bound to the peptide comprising residues 67−76 of EBOV VP35. Two VP35 peptides were found to interact with homodimeric LC8 by extending the central β- sheets, constituting a 2:2 complex. Structural analysis demonstrated that the intermolecular binding between LC8 and VP35 is mainly sustained by a network of hydrogen bonds and supported by hydrophobic interactions in which Thr73 and Thr75 of VP35 are involved. These findings were verified by binding measurements using isothermal titration calorimetry. Biochemical analyses also verified that residues 67−76 of EBOV VP35 constitute a core region for interaction with LC8. In addition, corresponding motifs from other members of the genus Ebolavirus commonly bound to LC8 but with different binding affinities. Particularly, VP35 peptides originating from pathogenic species interacted with LC8 with higher affinity than those from noninfectious species, suggesting that the binding of VP35 to LC8 is associated with the pathogenicity of the Ebolavirus species.

Citations

Citations to this article as recorded by

Crystal structures of the μ2 subunit of clathrin-adaptor protein 2 in complex with peptides derived from human papillomavirus 16 E7
Sujin Jung, Dahwan Lim, Joon Sig Choi, Ho-Chul Shin, Seung Jun Kim, Bonsu Ku
Journal of Microbiology.2025; 63(8): e2505003. CrossRef
Crystal Structures of Plk1 Polo-Box Domain Bound to the Human Papillomavirus Minor Capsid Protein L2-Derived Peptide
Sujin Jung, Hye Seon Lee, Ho-Chul Shin, Joon Sig Choi, Seung Jun Kim, Bonsu Ku
Journal of Microbiology.2023; 61(8): 755. CrossRef
Borna Disease Virus 1 Phosphoprotein Forms a Tetramer and Interacts with Host Factors Involved in DNA Double-Strand Break Repair and mRNA Processing
Nicolas Tarbouriech, Florian Chenavier, Junna Kawasaki, Kamel Bachiri, Jean-Marie Bourhis, Pierre Legrand, Lily L. Freslon, Estelle M. N. Laurent, Elsa Suberbielle, Rob W. H. Ruigrok, Keizo Tomonaga, Daniel Gonzalez-Dunia, Masayuki Horie, Etienne Coyaud,
Viruses.2022; 14(11): 2358. CrossRef
Structural and biochemical analysis of the PTPN4 PDZ domain bound to the C-terminal tail of the human papillomavirus E6 oncoprotein
Hye Seon Lee, Hye-Yeoung Yun, Eun-Woo Lee, Ho-Chul Shin, Seung Jun Kim, Bonsu Ku
Journal of Microbiology.2022; 60(4): 395. CrossRef

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