Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
Volume 1865, Issue 6, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbamem.2023.184174
Keywords
Transmembrane domain; RNA virus; Glycosylation; Molecular dynamics; Cellular immune response; SARS-CoV-2
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates within intracellular membranes. The virus employs transmembrane 'accessory' proteins like ORF7a to interfere with the antiviral protein BST-2. Mutations in the transmembrane domain of BST-2, such as I28S, can alter its interactions with ORF7a. Through molecular dynamics simulations, specific interfaces and interactions between BST-2 and ORF7a in the transmembrane region were identified, providing a structural basis for their interactions.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID, replicates at intracellular membranes. Bone marrow stromal antigen 2 (BST-2; tetherin) is an antiviral response protein that inhibits transport of viral particles after budding within infected cells. RNA viruses such as SARS-CoV-2 use various strategies to disable BST-2, including use of transmembrane 'accessory' proteins that interfere with BST-2 oligomerization. ORF7a is a small, transmembrane protein present in SARS-CoV-2 shown previously to alter BST -2 glycosylation and function. In this study, we investigated the structural basis for BST-2 ORF7a interactions, with a particular focus on transmembrane and juxtamembrane interactions. Our results indicate that trans -membrane domains play an important role in BST-2 ORF7a interactions and mutations to the transmembrane domain of BST-2 can alter these interactions, particularly single-nucleotide polymorphisms in BST-2 that result in mutations such as I28S. Using molecular dynamics simulations, we identified specific interfaces and interactions between BST-2 and ORF7a to develop a structural basis for the transmembrane interactions. Differences in glycosylation are observed for BST-2 transmembrane mutants interacting with ORF7a, consistent with the idea that transmembrane domains play a key role in their heterooligomerization. Overall, our results indicate that ORF7a transmembrane domain interactions play a key role along with extracellular and juxtamembrane domains in modulating BST-2 function.
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