Resilience of BST-2/Tetherin structure to single amino acid substitutions

Human Tetherin, also known as BST-2 or CD317, is a dimeric, extracellular membrane-bound protein that consists of N and C terminal membrane anchors connected by an extracellular domain. BST-2 is involved in binding enveloped viruses, such as HIV, and inhibiting viral release in addition to a role in NF-kB signaling. Viral tethering by Tetherin can be disrupted by the interaction with Vpu in HIV-1 in addition to other viral proteins. The structural mechanism of Tetherin function is not clear and the effects of human Tetherin mutations identified by sequencing consortiums are not known. To address this gap in the knowledge, we used data from the Ensembl database to construct and model known human missense mutations within the ectodomain to investigate how the structure of the ectodomain influences function. From the data, we identified an island of sequence stability within the ectodomain, which corresponds to functionally or structurally important region identified in previous biochemical and biophysical studies. Additionally, most mutations have little effect on structure, suggesting that they would not affect function. These findings are in agreement with biochemical and cellular studies which suggest that mutations that do not disrupt the alpha helices of Tetherin have little apparent effect on function. Thus, Tetherin sequence is likely less important than structure and this apparent flexibility may allow for greater anti-viral activities with a larger number of viruses.