Orf9b protein and tom70

The genome of human mitochondria codes for 37 proteins - the rest of the ca. 1500 needed proteins has to be imported from the cytosol. This requires a selective transport mechanism across inner and outer membranes of the mitochondria. In the context of corona infections one component of the transport mechanism is important: the receptor protein tom70 (translocase of the mitochondrial outer membrane). It not only discriminates the proteins to be imported to the mitochondria, but it reacts with a signal protein for viral infections (mitochondrial antiviral-signaling protein (MAVS)). MAVS is a component of the antiviral immune system.
Orf9b of cov2 is positioned within gene N (nuclear protein) and is transcribed by a reading frame shift. Orf9b protein binds to tom70.

The structure of yeast tom70 was elucidated some time ago, so the binding part for proteins (mostly in complex with chaperones = guiding proteins) is known. The secondary structure of human tom70 (here the space filling view: shown is the part protruding into the cytosol, the membrane spanning part is not visible) has some peculiarities . There is a repeating structural motiv consisting of two helices each, which are ordered antiparallel with an angel of 24° to each other. The first three repeats bind the chaperones . The next group of repeats is arranged to a superstructure . Now to the orf9b gene product: the protein binds in the gap (only amino acids 39 - 76 are visible). Under normal circumstances here will bind the signal sequences of proteins, which are transorted into the mitochondria without the help of chaperones. How is orf9b fastened? There are hydrophobic interactions (yellow) as well as electric forces between amino acids with charged atoms . Back to the complex . If binding of other proteins to tom70 should have any effect, tom70 must move: it reacts with conformational changes which then initiate further actions. The model shown here is static (at atomic level the movement of molecules evades detection). Only by comparison with "naked" tom70 (known from yeast) we can make deductions. In the unbound state tom70 has a more open structure; the tight grip on orf9b shown here occurs only after the initial binding of the viral protein. The effect: upon forming the complex the production of a group of interferons in our body is suppressed - the virus is free to multiply. Now, if we had something to prevent the binding of orf9b to tom70...

this demonstration.

Literature:
D E Gordon et al., Science 370 (2020) DOI: 10.1126/science.abe9403
S Kreimendahl, J Rassow, Int. J. Mol. Sci. 21, 7262 (2020) DOI:10.3390/ijms21197262