Highly versatile small virus-encoded proteins in cellular membranes: A structural perspective on how proteins’ inherent conformational plasticity couples with host membranes’ properties to control cellular processes

Figures

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  Fig. 1. Small viral proteins (viroporins) in host’s cell membranes. (A) These proteins reside and function in plasma and organelle membranes (e.g., membranes of ER and Golgi, and mitochondrial membranes). Furthermore, some of them are found in more than one membrane, e.g., IAM2 and Vpu are located in both plasma and endomembranes (ER and Golgi); P2B is found in endomembranes and outer mitochondrial membrane (OMM). The figure was created in BioRender. (B) The Classes I (1-TM helix) and II (2-TM helices) viroporins are shown; homo-oligomers are formed via TM helix-TM helix associations (only two protomers are shown for clarity).

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  Fig. 2. The amino acid sequences of the IAM2 (accession# P63231.1), HIV-1 Vpu (accession#NP_057855.1), CoV E (accession#YP_009724392.1), HTCLV-1 p13II (accession#AAB23362.1), HCV p7 (accession# YP-009709864.1, and P2B (accession# YP-009508946.1) are shown. The TM helices are highlighted in yellow and boxed. The region with positively charged residues in p13II’s sequence is highlighted in gray. The proteins were randomly selected aiming to demonstrate the distinct amino acid composition, particularly the composition of the TM helices, which associate to form ion-conducting channels or pores. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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  Fig. 3. The experimental and predicted structures of IAM2, HIV1 Vpu, CoV E, HICV p7, P2B and HTLV1 p13II proteins. (A) The NMR structure of IAM2 tetramer is shown. The TM helices are in green. The His37 and Thr41 critical for proton’s translocation are shown as sticks in blue and red, respectively. (B) The NMR structure of Vpu monomer (left) and AlphaFold-predicted structure of Vpu pentamer (right) are shown. The TM helices are in green. Based on the NMR structure, helix 2 (after TM helix) is bound to the membrane surface making almost 90° angle with TM helix 1; whereas, based on the AlphaFold prediction, helix 2 is almost a straight continuation of TM helix 1 outside of the membrane. These might correspond to different Vpu conformations, but further clarification would be necessary. Strikingly, all residues in TM helix facing the pentamer interior are highly hydrophobic, and how the channel/pore might transport ions is currently unclear. (C) The NMR structures of pentameric E protein TM domain in closed and open conformations are overlayed (left). The experimental results suggest that local restructuring, including helix rotation, at and around residue Asn15 leads to channel/pore…