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Structure of Epstein-Barr Virus Tegument Protein Complex BBRF2-BSRF1 Reveals Its Potential Role in Viral Envelopment

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Structure of Epstein-Barr Virus Tegument Protein Complex BBRF2-BSRF1 Reveals Its Potential Role in Viral Envelopment ARTICLE https://doi.org/10.1038/s41467-020-19259-x OPEN Structure of Epstein-Barr virus tegument protein complex BBRF2-BSRF1 reveals its potential role in viral envelopment Hui-Ping He1,4, Meng Luo1,4, Yu-Lu Cao 1, Yu-Xin Lin1, Hua Zhang1, Xiao Zhang1, Jun-Ying Ou1, Bing Yu1, ✉ Xiaoxue Chen 2, Miao Xu1, Lin Feng 1, Mu-Sheng Zeng 1, Yi-Xin Zeng 1 & Song Gao 1,3 γ 1234567890():,; Epstein-Barr virus (EBV) is a -herpesvirus associated with the occurrence of several human malignancies. BBRF2 and BSRF1 are two EBV tegument proteins that have been suggested to form a hetero-complex and mediate viral envelopment, but the molecular basis of their interaction and the functional mechanism of this complex remains unknown. Here, we pre- sent crystal structures of BBRF2 alone and in complex with BSRF1. BBRF2 has a compact globular architecture featuring a central β-sheet that is surrounded by 10 helices, it represents a novel fold distinct from other known protein structures. The central portion of BSRF1 folds into two tightly associated antiparallel α-helices, forming a composite four-helix bundle with two α-helices from BBRF2 via a massive hydrophobic network. In vitro, a BSRF1-derived peptide binds to BBRF2 and reduces the number of viral genome copies in EBV-positive cells. Exogenous BBRF2 and BSRF1 co-localize at the Golgi apparatus. Furthermore, BBRF2 binds capsid and capsid-associated proteins, whereas BSRF1 associates with glycoproteins. These findings indicate that the BBRF2-BSRF1 complex tethers EBV nucleocapsids to the glycoprotein-enriched Golgi membrane, facilitating secondary envelopment. 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060 Guangzhou, China. 2 Molecular Imaging Center, Guangdong Provincial Key Laboratory of Biomedical Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, 519000 Zhuhai, China. 3 Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 510530 Guangzhou, China. 4These authors ✉ contributed equally: Hui-Ping He, Meng Luo. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:5405 | https://doi.org/10.1038/s41467-020-19259-x | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19259-x pstein-Barr virus (EBV) is a double-stranded DNA virus In herpesviruses, the space between the nucleocapsid and the Ethat is carried by ~95% of the human population. EBV envelope is called the tegument. The EBV genome contains over infects B lymphocytes and epithelial cells, and can persist 80 reading frames, more than 10 of which encode proteins that throughout life with alternate periods of latency state and lytic reside in the tegument and, thus, are termed tegument replication1,2. EBV infection usually results in a mild, if any, proteins5,10. Tegument proteins are engaged in viral morpho- pathogenic effect in healthy individuals. In a few cases, it causes genesis, envelopment, egress, evasion from host immune sur- acute infectious mononucleosis, particularly upon the first veillance, and in preparing and reprogramming the cell for viral exposure in adolescents and adulthood3. In immunosuppressed replication11. Other viral gene products including the surface individuals, such as AIDS patients and transplant recipients, EBV glycoproteins and transcription factors have been studied can cause fatal lymphoproliferative disease4. Another life- extensively12,13, but structural information and functional threatening issue of EBV is that it is an oncogenic virus closely mechanisms for the majority of EBV tegument proteins, includ- associated with several human malignancies, including Burkitt’s ing BBRF2 and BSRF1, remain elusive. lymphoma, Hodgkin’s lymphoma, T/NK cell lymphoma, gastric BBRF2 is an EBV tegument protein that has putative homo- carcinoma, and nasopharyngeal carcinoma5,6. Currently, no logues in all three herpesvirus subfamilies10. BBRF2 was recently effective clinical approach is available to prevent or eliminate shown to be a binding partner of BSRF1, another poorly char- EBV infection. acterized EBV tegument protein14. Complexing of the two pro- EBV belongs to the Herpesviridae family, which is comprised teins alters the subcellular localization of BBRF2, and prevents of α-, β-, and γ-subfamilies7. Representatives of the ɑ- BSRF1 from degradation, which ultimately augments viral herpesvirinae are HSV-1 and HSV-2, which are common infectivity15. The BBRF2 homologue in KSHV, ORF42, has been human-infecting pathogens that have been extensively studied. shown to be required for efficient production of viral particles, The β-herpesvirus subfamily includes human cytomegalovirus but is dispensable for reactivation of the lytic cycle16. Tegument (HCMV). EBV and Kaposi’s Sarcoma (KSHV) are members of proteins pUL7 in HSV and pUL103 in HCMV, which are the γ-herpesvirinae. Herpesviruses share a common virion mor- homologues of BBRF2 in α- and β-herpesviruses, have been phology and feature two steps of envelopment before egress. The reported to have similar roles in viral assembly and egress17,18. nascent herpesvirus nucleocapsids assembled in host cell nuclei These BBRF2 homologues in three herpesvirus subfamilies also translocate to the cytoplasm via primary envelopment/de-envel- exhibit other specific functions. ORF42 appears to post- opment at the nuclear membrane8. These capsids then undergo a transcriptionally regulate the expression of some viral genes in secondary envelopment to acquire envelope from host organelles, KSHV16. The BBRF2-BSRF1 interaction seems to be conserved particularly the Golgi apparatus where the viral glycoproteins across herpesviruses, as homologous interactions have been reside9. The exact mechanism of herpesvirus secondary envel- reported for HSV-1 (pUL7-pUL51)12 and HCMV (pUL103- opment is not fully understood. pUL71)19. In HSV-1, the pUL7-pUL51 complex is required to promote the assembly and cell-to-cell spread of virions, and potentially also to stabilize focal adhesions12,17,20. However, the Table 1 Crystallographic data collection and refinement. exact function of EBV BBRF2 is not fully understood, and the molecular basis of the interaction between BBRF2 and BSRF1 is BBRF2Δ BBRF2Δ-BSRF1Δ unclear, partly due to the lack of structural information. complex Here, we report crystal structures of BBRF2 alone and in Data collection complex with BSRF1. BBRF2 has a compact globular architecture Space group P21212P21 that represents a novel fold different from other known protein Cell dimensions structures. The central part of BSRF1 folds into two tightly a, b, c (Å) 73.318, 61.571, 58.109 75.78, 161.85, 97.86 associated antiparallel α-helices, which form a heterogeneous α, β, γ (°) 90, 90, 90 90, 100.8, 90 four-helix bundle with two α-helices from BBRF2 via hydro- Wavelength (Å) 0.97915 0.97853 phobic interactions. This interface can be disrupted by a BSRF1- a – – – – Resolution (Å) 47.15 1.6 (1.69 1.6) 48.07 3.09 (3.28 3.09) derived peptide. The BBRF2-BSRF1 complex resides on the Golgi Total reflections 248,156 (39,396) 145,743 (21,580) apparatus. BBRF2 binds EBV capsid protein MCP and capsid- Unique reflections 66,863 (10,656) 42,196 (6720) associated protein BPLF1, whereas BSRF1 associates with EBV Rsym 0.072 (0.575) 0.082 (0.495) I/σ(I) 13.39 (3.98) 13.27 (2.23) glycoproteins gB and gH/gL. These data elucidate the molecular Completeness (%) 99.1 (97.5) 99.4 (98.3) basis of the functional association between BBRF2 and BSRF1, Redundancy 3.71 (3.7) 3.45 (3.21) suggesting a role of BBRF2-BSRF1 in tethering EBV nucleo- Refinement capsids to the Golgi membrane during secondary envelopment. Rwork/Rfree 0.166/0.189 0.217/0.27 No. of atoms Protein 2153 16,133 Results Ligand/ion 14 30 Overall structure of BBRF2. To obtain functional insights into Water 278 28 BBRF2, we recombinantly expressed the protein in Escherichia B-factors coli and purified it. BBRF2 is a monomer in solution (Supple- Protein 23.15 75.67 mentary Fig. 1a). As crystallization of full-length BBRF2 was not Ligand/ion 56.60 65.38 fi Water 37.23 44.86 successful, we modi ed the construct and determined the struc- R.m.s. deviations ture of an N- terminally truncated version with deletion of resi- − Δ Bond lengths (Å) 0.009 0.009 dues 1 16 (BBRF2 ) at 1.6 Å. The phases were obtained by Bond angles (°) 1.11 1.10 single anomalous diffraction using selenomethionine (SeMet) fi fi Ramachandran derivative, and the nal model was re ned to an Rfree of 0.189 Favoured (%) 98.5 92.0 (Table 1). ΒΒRF2Δ is monomeric both in solution and in the Outliers (%) 0 1.1 asymmetric unit of the crystal (Supplementary Fig. 1b). Residues of the whole crystallized construct, including those encoded by aNumbers in parentheses are values from the highest resolution shell. the vector sequence, except for 172–178, are clearly seen in the 2 NATURE COMMUNICATIONS | (2020) 11:5405 | https://doi.org/10.1038/s41467-020-19259-x | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19259-x ARTICLE a b 169 129 123 199 196 α4 α5 α4 α3 α α α α 7 6 1 C 5 209 186 149 α 146 109 3 56 68 β1 N α1 β β2 5 β4 233 240 38 35 73 104 β3 α β β β β α2 α6 8 6 3 2 5 η1 β6 α9 β 244 4 222 42 30 101 100 α8 α7 27 256 η1 257 251 α2 90° β1 94 α9 α4 268 24 80 C N α1 α3 C α5 c η1 β N123 β 1 N 4 β5 L249O β2 O H O V87O α3 H O 2 β3 90° 2 α6 β2 H253 The V87N α2 90° V29O E122 bulged β6 η loop 1 α9 V29N L28N α9 R27 D85 N86N α8 α 7 β 4 β1 Fig.
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