Site-Specific Lipidation Enhances IFITM3 Membrane Interactions and Antiviral Activity

• Published in: ACS chemical biology Vol. 16; no. 5; pp. 844 - 856
• Main Authors: Garst, Emma H, Lee, Hwayoung, Das, Tandrila, Bhattacharya, Shibani, Percher, Avital, Wiewiora, Rafal, Witte, Isaac P, Li, Yumeng, Peng, Tao, Im, Wonpil, Hang, Howard C
• Format: Journal Article
• Language: English
• Published: United States 21-05-2021
• Subjects: 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
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.1c00013

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.