Site-Specific Lipidation Enhances IFITM3 Membrane Interactions and Antiviral Activity
Interferon-induced transmembrane proteins (IFITMs) are -palmitoylated proteins in vertebrates that restrict a diverse range of viruses. -palmitoylated IFITM3 in particular engages incoming virus particles, prevents their cytoplasmic entry, and accelerates their lysosomal clearance by host cells. How...
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Published in: | ACS chemical biology Vol. 16; no. 5; pp. 844 - 856 |
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Abstract | Interferon-induced transmembrane proteins (IFITMs) are
-palmitoylated proteins in vertebrates that restrict a diverse range of viruses.
-palmitoylated IFITM3 in particular engages incoming virus particles, prevents their cytoplasmic entry, and accelerates their lysosomal clearance by host cells. However, how
-palmitoylation modulates the structure and biophysical characteristics of IFITM3 to promote its antiviral activity remains unclear. To investigate how site-specific
-palmitoylation controls IFITM3 antiviral activity, we employed computational, chemical, and biophysical approaches to demonstrate that site-specific lipidation of cysteine 72 enhances the antiviral activity of IFITM3 by modulating its conformation and interaction with lipid membranes. Collectively, our results demonstrate that site-specific
-palmitoylation of IFITM3 directly alters its biophysical properties and activity in cells to prevent virus infection. |
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AbstractList | Interferon-induced transmembrane proteins (IFITMs) are
S
-palmitoylated proteins in vertebrates that restrict a diverse range of viruses.
S
-palmitoylated IFITM3 in particular engages incoming virus particles, prevents their cytoplasmic entry, and accelerates their lysosomal clearance by host cells. However, how
S
-palmitoylation modulates the structure and biophysical characteristics of IFITM3 to promote its antiviral activity remains unclear. To investigate how site-specific
S
-palmitoylation controls IFITM3 antiviral activity, we employed computational, chemical, and biophysical approaches to demonstrate that site-specific lipidation of cysteine 72 enhances the antiviral activity of IFITM3 by modulating its conformation and interaction with lipid membranes. Collectively, our results demonstrate that site-specific
S
-palmitoylation of IFITM3 directly alters its biophysical properties and activity in cells to prevent virus infection. Interferon-induced transmembrane proteins (IFITMs) are -palmitoylated proteins in vertebrates that restrict a diverse range of viruses. -palmitoylated IFITM3 in particular engages incoming virus particles, prevents their cytoplasmic entry, and accelerates their lysosomal clearance by host cells. However, how -palmitoylation modulates the structure and biophysical characteristics of IFITM3 to promote its antiviral activity remains unclear. To investigate how site-specific -palmitoylation controls IFITM3 antiviral activity, we employed computational, chemical, and biophysical approaches to demonstrate that site-specific lipidation of cysteine 72 enhances the antiviral activity of IFITM3 by modulating its conformation and interaction with lipid membranes. Collectively, our results demonstrate that site-specific -palmitoylation of IFITM3 directly alters its biophysical properties and activity in cells to prevent virus infection. |
Author | Im, Wonpil Percher, Avital Li, Yumeng Bhattacharya, Shibani Peng, Tao Lee, Hwayoung Das, Tandrila Wiewiora, Rafal Witte, Isaac P Garst, Emma H Hang, Howard C |
AuthorAffiliation | 1 Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, New York 10065, United States 2 Tri-Institutional Ph.D. Program in Chemical Biology, New York, NY 10065, United States 5 Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States 7 Departments of Immunology and Microbiology and Chemistry, Scripps Research, La Jolla, CA 92037, United States 6 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China 3 Department of Biological Sciences, Chemistry, and Bioengineering, Lehigh University, Bethlehem, PA 18015, United States 4 New York Structural Biology Center, New York, NY 10027, United States |
AuthorAffiliation_xml | – name: 2 Tri-Institutional Ph.D. Program in Chemical Biology, New York, NY 10065, United States – name: 6 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China – name: 7 Departments of Immunology and Microbiology and Chemistry, Scripps Research, La Jolla, CA 92037, United States – name: 1 Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, New York 10065, United States – name: 4 New York Structural Biology Center, New York, NY 10027, United States – name: 3 Department of Biological Sciences, Chemistry, and Bioengineering, Lehigh University, Bethlehem, PA 18015, United States – name: 5 Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States |
Author_xml | – sequence: 1 givenname: Emma H orcidid: 0000-0001-8170-2343 surname: Garst fullname: Garst, Emma H organization: Tri-Institutional Ph.D. Program in Chemical Biology, New York, New York 10065, United States – sequence: 2 givenname: Hwayoung orcidid: 0000-0003-2332-1993 surname: Lee fullname: Lee, Hwayoung organization: Department of Biological Sciences, Chemistry, and Bioengineering, Lehigh University, Bethlehem, Pennsylvania 18015, United States – sequence: 3 givenname: Tandrila surname: Das fullname: Das, Tandrila organization: Tri-Institutional Ph.D. Program in Chemical Biology, New York, New York 10065, United States – sequence: 4 givenname: Shibani surname: Bhattacharya fullname: Bhattacharya, Shibani organization: New York Structural Biology Center, New York, New York 10027, United States – sequence: 5 givenname: Avital surname: Percher fullname: Percher, Avital organization: Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, New York 10065, United States – sequence: 6 givenname: Rafal orcidid: 0000-0002-8961-7183 surname: Wiewiora fullname: Wiewiora, Rafal organization: Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States – sequence: 7 givenname: Isaac P surname: Witte fullname: Witte, Isaac P organization: Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, New York 10065, United States – sequence: 8 givenname: Yumeng surname: Li fullname: Li, Yumeng organization: State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China – sequence: 9 givenname: Tao orcidid: 0000-0002-5578-5314 surname: Peng fullname: Peng, Tao organization: State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China – sequence: 10 givenname: Wonpil orcidid: 0000-0001-5642-6041 surname: Im fullname: Im, Wonpil organization: Department of Biological Sciences, Chemistry, and Bioengineering, Lehigh University, Bethlehem, Pennsylvania 18015, United States – sequence: 11 givenname: Howard C orcidid: 0000-0003-4053-5547 surname: Hang fullname: Hang, Howard C organization: Departments of Immunology and Microbiology and Chemistry, Scripps Research, La Jolla, California 92037, United States |
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Notes | These authors contributed equally. |
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Snippet | Interferon-induced transmembrane proteins (IFITMs) are
-palmitoylated proteins in vertebrates that restrict a diverse range of viruses.
-palmitoylated IFITM3... Interferon-induced transmembrane proteins (IFITMs) are S -palmitoylated proteins in vertebrates that restrict a diverse range of viruses. S -palmitoylated... |
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SubjectTerms | Amino Acid Sequence Antiviral Agents - chemistry Antiviral Agents - pharmacology Binding Sites Cell Membrane - metabolism Cell Membrane - ultrastructure Computational Biology Drug Design Humans Interferons - chemistry Interferons - pharmacology Lipids - chemistry Lipoylation Lysosomes - metabolism Membrane Proteins - metabolism Molecular Dynamics Simulation Protein Binding Protein Conformation RNA-Binding Proteins - metabolism Signal Transduction |
Title | Site-Specific Lipidation Enhances IFITM3 Membrane Interactions and Antiviral Activity |
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