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In the absence of viral antagonism, Serinc3 and Serinc5 incorporate into the envelopes of nascent virions and inhibit the fusion of virions to the target cells. The HIV-1 virus counteracts the restriction of Serinc3 by downregulating it from the cell surface and thus excluding it from budding virions. This is orchestrated by the viral accessory protein Nef and involves hijacking of the clathrin adaptor protein complex 2 (AP2)-dependent endocytosis. The mechanistic details of Nef-mediated Serinc3 downregulation, however, have been enigmatic. In this work, we investigated and revealed the molecular determinants of Serinc3 modulation by Nef. Our results show that Nef recruits Serinc3 by binding to its N-terminal cytosolic tail. Furthermore, Nef residues important for Serinc3-binding in vitro, and for the exclusion of Serinc3 from virions, overlap with those required for Nef-mediated CD4 downregulation, suggesting great mechanistic similarities between the two functions of Nef. In addition to shedding light on the mechanism of Serinc3 antagonism, our work also highlights the conserved substrate-binding pocket of Nef as a molecular hotspot for inhibitor development and antiretroviral drug discovery.<\/jats:p>","DOI":"10.3390\/v18010005","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T14:27:16Z","timestamp":1766154436000},"page":"5","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HIV-1 Nef Uses a Conserved Pocket to Recruit the N-Terminal Cytoplasmic Tail of Serinc3"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3392-9951","authenticated-orcid":false,"given":"Mohammad","family":"Karimian Shamsabadi","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, Dartmouth, MA 02747, USA"},{"name":"The Biomedical Engineering and Biotechnology Program, University of Massachusetts Dartmouth, Dartmouth, MA 02747, USA"},{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3729-6936","authenticated-orcid":false,"given":"Charlotte","family":"Stoneham","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA"},{"name":"The VA San Diego Healthcare System, San Diego, CA 92161, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amalia","family":"De Leon","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA"},{"name":"The VA San Diego Healthcare System, San Diego, CA 92161, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tony","family":"Fares","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, Dartmouth, MA 02747, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Guatelli","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA"},{"name":"The VA San Diego Healthcare System, San Diego, CA 92161, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0972-3884","authenticated-orcid":false,"given":"Xiaofei","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"35776","DOI":"10.1074\/jbc.M505712200","article-title":"Serinc, an activity-regulated protein family, incorporates serine into membrane lipid synthesis","volume":"280","author":"Inuzuka","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s00430-022-00732-x","article-title":"HIV-1 restriction by SERINC5","volume":"212","author":"Luedde","year":"2023","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nature15399","article-title":"HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation","volume":"526","author":"Rosa","year":"2015","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/nature15400","article-title":"SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef","volume":"526","author":"Usami","year":"2015","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6014","DOI":"10.1074\/jbc.M117.777714","article-title":"SERINC5 protein inhibits HIV-1 fusion pore formation by promoting functional inactivation of envelope glycoproteins","volume":"292","author":"Sood","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15183","DOI":"10.1074\/jbc.RA120.014466","article-title":"HIV-cell membrane fusion intermediates are restricted by Serincs as revealed by cryo-electron and TIRF microscopy","volume":"295","author":"Ward","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e00544-19","DOI":"10.1128\/JVI.00544-19","article-title":"CD4 Expression and Env Conformation Are Critical for HIV-1 Restriction by SERINC5","volume":"93","author":"Zhang","year":"2019","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/JVI.02214-16","article-title":"Effect of HIV-1 Env on SERINC5 Antagonism","volume":"91","author":"Beitari","year":"2017","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lai, R.P., Yan, J., Heeney, J., McClure, M.O., Gottlinger, H., Luban, J., and Pizzato, M. (2011). Nef decreases HIV-1 sensitivity to neutralizing antibodies that target the membrane-proximal external region of TMgp41. PLoS Pathogen., 7.","DOI":"10.1371\/journal.ppat.1002442"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e00594-20.","DOI":"10.1128\/JVI.00594-20","article-title":"SERINC5 Inhibits HIV-1 Infectivity by Altering the Conformation of gp120 on HIV-1 Particles","volume":"94","author":"Featherstone","year":"2020","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13702","DOI":"10.1074\/jbc.M117.797332","article-title":"The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles","volume":"292","author":"Trautz","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4368","DOI":"10.1038\/s41467-023-39262-2","article-title":"Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry","volume":"14","author":"Leonhardt","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_13","first-page":"147","article-title":"Implications of Nef: Host cell interactions in viral persistence and progression to AIDS","volume":"339","author":"Arhel","year":"2009","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27029","DOI":"10.1074\/jbc.M601128200","article-title":"HIV-1 Nef selectively activates Src family kinases Hck, Lyn, and c-Src through direct SH3 domain interaction","volume":"281","author":"Trible","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15718","DOI":"10.1074\/jbc.M114.572099","article-title":"The Accessory Factor Nef Links HIV-1 to Tec\/Btk Kinases in an Src Homology 3 Domain-dependent Manner","volume":"289","author":"Tarafdar","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1111\/tra.12412","article-title":"HIV-1 Nef: Taking Control of Protein Trafficking","volume":"17","author":"Pereira","year":"2016","journal-title":"Traffic"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/S0960-9822(99)80284-X","article-title":"Cell-surface expression of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner","volume":"9","author":"Lama","year":"1999","journal-title":"Curr. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1742-4690-11-15","article-title":"HIV Nef and Vpu protect HIV-infected CD4+ T cells from antibody-mediated cell lysis through down-modulation of CD4 and BST2","volume":"11","author":"Pham","year":"2014","journal-title":"Retrovirology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1128\/JVI.03230-13","article-title":"Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity","volume":"88","author":"Veillette","year":"2014","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e01403-19","DOI":"10.1128\/JVI.01403-19","article-title":"CD4 Incorporation into HIV-1 Viral Particles Exposes Envelope Epitopes Recognized by CD4-Induced Antibodies","volume":"93","author":"Ding","year":"2019","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/34929","article-title":"HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes","volume":"391","author":"Collins","year":"1998","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6964","DOI":"10.1093\/emboj\/16.23.6964","article-title":"Co-localization of HIV-1 Nef with the AP-2 adaptor protein complex correlates with Nef-induced CD4 down-regulation","volume":"16","author":"Greenberg","year":"1997","journal-title":"Embo J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.1128\/JVI.02725-06","article-title":"Downregulation of CD4 by human immunodeficiency virus type 1 Nef is dependent on clathrin and involves direct interaction of Nef with the AP2 clathrin adaptor","volume":"81","author":"Chaudhuri","year":"2007","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1083\/jcb.200407031","article-title":"HIV-1 Nef disrupts MHC-1 trafficking by recruiting AP-1 to the MHC-1 cytoplasmic tail","volume":"167","author":"Roeth","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1128\/JVI.00660-07","article-title":"Cooperative binding of the class I major histocompatibility complex cytoplasmic domain and human immunodeficiency virus type 1 Nef to the endosomal AP-1 complex via its mu subunit","volume":"82","author":"Noviello","year":"2008","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.1074\/jbc.M707760200","article-title":"The tyrosine binding pocket in the adaptor protein 1 (AP-1) mu 1 subunit is necessary for nef to recruit AP-1 to the major histocompatibility complex class I cytoplasmic tail","volume":"283","author":"Wonderlich","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Singh, R.K., Lau, D., Noviello, C.M., Ghosh, P., and Guatelli, J.C. (2009). An MHC-I Cytoplasmic Domain\/HIV-1 Nef Fusion Protein Binds Directly to the mu Subunit of the AP-1 Endosomal Coat Complex. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0008364"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11229","DOI":"10.1073\/pnas.95.19.11229","article-title":"Interaction of HIV-1 Nef with the cellular dileucine-based sorting pathway is required for CD4 down-regulation and optimal viral infectivity","volume":"95","author":"Craig","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6812","DOI":"10.1073\/pnas.0607622104","article-title":"Dynamin 2 is required for the enhancement of HIV-1 infectivity by Nef","volume":"104","author":"Pizzato","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"a016790","DOI":"10.1101\/cshperspect.a016790","article-title":"Cargo recognition in clathrin-mediated endocytosis","volume":"5","author":"Traub","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e01754","DOI":"10.7554\/eLife.01754","article-title":"How HIV-1 Nef hijacks the AP-2 clathrin adaptor to downregulate CD4","volume":"3","author":"Ren","year":"2014","journal-title":"eLife"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/s41594-020-0463-z","article-title":"Structural basis of CD4 downregulation by HIV-1 Nef","volume":"27","author":"Kwon","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1006\/viro.1997.8517","article-title":"Identification of regions in HIV-1 Nef required for efficient downregulation of cell surface CD4","volume":"231","author":"Hua","year":"1997","journal-title":"Virology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5310","DOI":"10.1128\/JVI.74.11.5310-5319.2000","article-title":"Mutation of a conserved residue (D123) required for oligomerization of human immunodeficiency virus type 1 Nef protein abolishes interaction with human thioesterase and results in impairment of Nef biological functions","volume":"74","author":"Liu","year":"2000","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.jmb.2009.09.047","article-title":"HIV-1 Nef dimerization is required for Nef-mediated receptor downregulation and viral replication","volume":"394","author":"Poe","year":"2009","journal-title":"J. Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1128\/JVI.73.3.1964-1973.1999","article-title":"Nef-induced CD4 and major histocompatibility complex class I (MHC-I) down-regulation are governed by distinct determinants: N-terminal alpha helix and proline repeat of Nef selectively regulate MHC-I trafficking","volume":"73","author":"Mangasarian","year":"1999","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.celrep.2017.12.082","article-title":"A Long Cytoplasmic Loop Governs the Sensitivity of the Anti-viral Host Protein SERINC5 to HIV-1 Nef","volume":"22","author":"Dai","year":"2018","journal-title":"Cell Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"15540","DOI":"10.1074\/jbc.RA120.014668","article-title":"Nef homodimers down-regulate SERINC5 by AP-2-mediated endocytosis to promote HIV-1 infectivity","volume":"295","author":"Staudt","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00196-18","DOI":"10.1128\/JVI.00196-18","article-title":"HIV-1 Nef Antagonizes SERINC5 Restriction by Downregulation of SERINC5 via the Endosome\/Lysosome System","volume":"92","author":"Shi","year":"2018","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e01398-19","DOI":"10.1128\/JVI.01398-19","article-title":"Multifunctional Roles of the N-Terminal Region of HIV-1SF2Nef Are Mediated by Three Independent Protein Interaction Sites","volume":"94","author":"Ananth","year":"2019","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Firrito, C., Bertelli, C., Rosa, A., Chande, A., Ananth, S., van Dijk, H., Fackler, O.T., Stoneham, C., Singh, R., and Guatelli, J. (2023). A Conserved Acidic Residue in the C-Terminal Flexible Loop of HIV-1 Nef Contributes to the Activity of SERINC5 and CD4 Downregulation. Viruses, 15.","DOI":"10.3390\/v15030652"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4112","DOI":"10.1128\/jvi.69.7.4112-4121.1995","article-title":"Dissociation of the Cd4 down-Regulation and Viral Infectivity Enhancement Functions of Human-Immunodeficiency-Virus Type-1 Nef","volume":"69","author":"Goldsmith","year":"1995","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e0058821","DOI":"10.1128\/JVI.00588-21","article-title":"An Amino Acid Polymorphism within the HIV-1 Nef Dileucine Motif Functionally Uncouples Cell Surface CD4 and SERINC5 Downregulation","volume":"95","author":"Mumby","year":"2021","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e23","DOI":"10.1097\/QAI.0000000000002418","article-title":"Patient-Derived HIV-1 Nef Alleles Reveal Uncoupling of CD4 Downregulation and SERINC5 Antagonism Functions of the Viral Pathogenesis Factor","volume":"85","author":"Obermaier","year":"2020","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e01911-20","DOI":"10.1128\/JVI.01911-20","article-title":"Selective Disruption of SERINC5 Antagonism by Nef Impairs SIV Replication in Primary CD4+ T Cells","volume":"95","author":"Janaka","year":"2021","journal-title":"J. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"107528","DOI":"10.1016\/j.jbc.2024.107528","article-title":"A fluorescence polarization assay for high-throughput screening of inhibitors against HIV-1 Nef-mediated CD4 downregulation","volume":"300","author":"Jia","year":"2024","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1021\/bc7002499","article-title":"Efficient site-specific labeling of proteins via cysteines","volume":"19","author":"Kim","year":"2008","journal-title":"Bioconjug. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15678","DOI":"10.1074\/jbc.RA118.003080","article-title":"Phosphoserine acidic cluster motifs bind distinct basic regions on the mu subunits of clathrin adaptor protein complexes","volume":"293","author":"Singh","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1128\/jvi.59.2.284-291.1986","article-title":"Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone","volume":"59","author":"Adachi","year":"1986","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1128\/jvi.68.5.2906-2914.1994","article-title":"Optimal Infectivity in-Vitro of Human-Immunodeficiency-Virus Type-1 Requires an Intact Nef Gene","volume":"68","author":"Chowers","year":"1994","journal-title":"J. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1084\/jem.179.1.115","article-title":"The Importance of Nef in the Induction of Human-Immunodeficiency-Virus Type-1 Replication from Primary Quiescent Cd4 Lymphocytes","volume":"179","author":"Spina","year":"1994","journal-title":"J. Exp. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/nsmb.2328","article-title":"Structural basis of evasion of cellular adaptive immunity by HIV-1 Nef","volume":"19","author":"Jia","year":"2012","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.chom.2019.08.002","article-title":"Structural Basis for Tetherin Antagonism as a Barrier to Zoonotic Lentiviral Transmission","volume":"26","author":"Buffalo","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Barone, M.E., Lim, A., Woody, M., Taklifi, P., Yeasmin, F., Wang, K., Lewinski, M.K., Singh, R., Stoneham, C.A., and Jia, X. (2025). Adaptor Protein Complexes in HIV-1 Pathogenesis: Mechanisms and Therapeutic Potential. Viruses, 17.","DOI":"10.20944\/preprints202504.0804.v1"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1128\/JVI.79.1.632-636.2005","article-title":"Human immunodeficiency virus type 1 Nef domains required for disruption of major histocompatibility complex class I trafficking are also necessary for coprecipitation of Nef with HLA-A2","volume":"79","author":"Williams","year":"2005","journal-title":"J. Virol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1128\/JVI.80.3.1311-1320.2006","article-title":"Dynamic evolution of the human immunodeficiency virus type 1 pathogenic factor, Nef","volume":"80","author":"Kuo","year":"2006","journal-title":"J. Virol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"19416","DOI":"10.1038\/s41598-020-76375-w","article-title":"Impaired ability of Nef to counteract SERINC5 is associated with reduced plasma viremia in HIV-infected individuals","volume":"10","author":"Toyoda","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e0338222","DOI":"10.1128\/mbio.03382-22","article-title":"AP-2 Adaptor Complex-Dependent Enhancement of HIV-1 Replication by Nef in the Absence of the Nef\/AP-2 Targets SERINC5 and CD4","volume":"14","author":"Olety","year":"2023","journal-title":"mBio"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Breuer, S., Schievink, S.I., Schulte, A., Blankenfeldt, W., Fackler, O.T., and Geyer, M. (2011). Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020033"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"28539","DOI":"10.1074\/jbc.M114.600031","article-title":"Interaction with the Src homology (SH3-SH2) region of the Src-family kinase Hck structures the HIV-1 Nef dimer for kinase activation and effector recruitment","volume":"289","author":"Alvarado","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1128\/JVI.02227-08","article-title":"A Basic Patch on alpha-Adaptin Is Required for Binding of Human Immunodeficiency Virus Type 1 Nef and Cooperative Assembly of a CD4-Nef-AP-2 Complex","volume":"83","author":"Chaudhuri","year":"2009","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/s41594-019-0357-0","article-title":"A bipartite structural organization defines the SERINC family of HIV-1 restriction factors","volume":"27","author":"Pye","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e105492","DOI":"10.15252\/embj.2020105492","article-title":"Unbiased proteomic profiling of host cell extracellular vesicle composition and dynamics upon HIV-1 infection","volume":"40","author":"Nevo","year":"2021","journal-title":"Embo J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"100676","DOI":"10.1016\/j.mcpro.2023.100676","article-title":"HIV-1 Nef Changes the Proteome of T Cells Extracellular Vesicles Depleting IFITMs and Other Antiviral Factors","volume":"22","author":"Tavares","year":"2023","journal-title":"Mol. Cell Proteom."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Jin, S.W., Mwimanzi, F.M., Mann, J.K., Bwana, M.B., Lee, G.Q., Brumme, C.J., Hunt, P.W., Martin, J.N., Bangsberg, D.R., and Ndung\u2019u, T. (2020). Variation in HIV-1 Nef function within and among viral subtypes reveals genetically separable antagonism of SERINC3 and SERINC5. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008813"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Kruize, Z., van Nuenen, A.C., van Wijk, S.W., Girigorie, A.F., van Dort, K.A., Booiman, T., and Kootstra, N.A. (2021). Nef Obtained from Individuals with HIV-1 Vary in Their Ability to Antagonize SERINC3- and SERINC5-Mediated HIV-1 Restriction. Viruses, 13.","DOI":"10.3390\/v13030423"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/1\/5\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T05:28:10Z","timestamp":1766294890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/1\/5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,19]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["v18010005"],"URL":"https:\/\/doi.org\/10.3390\/v18010005","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2025,12,19]]}}}