New SARS-CoV-2 receptor

SARS-CoV-2 has a broad tissue tropism. In Cell, Baggen et al. show that the lysosomal transmembrane protein TMEM106B directly engages the receptor-binding domain (RBD) of the viral spike protein and functions as a receptor for SARS-CoV-2. E484D substitutions in the spike protein, which are detected in circulating SARS-CoV-2 isolates, increase SARS-CoV-2 infection in a manner dependent on TMEM106B, but not ACE2, while antibodies to TMEM106B block SARS-CoV-2 entry in ACE2− cells. Using cryo-electron microscopy and hydrogen–deuterium exchange mass spectrometry, the authors show that region 443–495 of the RBD, which also binds to ACE2, represents the binding platform for TMEM106B. TMEM106 binds the S1 subunit of the spike protein at Asp484 with a dissociation constant of around 20–14 μM, and is outcompeted by ACE2, which binds RBD with higher affinity. TMEM106B from human, mouse, hamster and monkey all mediate SARS-CoV-2 infection to a similar extent, and TMEM106B supports the infection of cells with low or undetectable expression of ACE2, such as astrocytes, which suggests that TMEM106B could mediate the infection of ACE2– cells in a variety of tissues.

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