Inconspicuous yet indispensable: the coronavirus spike transmembrane domain

International Journal of Molecular Sciences. 2023. Vol. 24. No. 22. Article 16421.

Aliper E., Roman G. Efremov

Membrane-spanning portions of proteins’ polypeptide chains are commonly known as
their transmembrane domains (TMDs). The structural organisation and dynamic behaviour of TMDs
from proteins of various families, be that receptors, ion channels, enzymes etc., have been under
scrutiny on the part of the scientific community for the last few decades. The reason for such attention
is that, apart from their obvious role as an “anchor” in ensuring the correct orientation of the protein’s
extra-membrane domains (in most cases functionally important), TMDs often actively and directly
contribute to the operation of “the protein machine”. They are capable of transmitting signals across
the membrane, interacting with adjacent TMDs and membrane-proximal domains, as well as with
various ligands, etc. Structural data on TMD arrangement are still fragmentary at best due to their
complex molecular organisation as, most commonly, dynamic oligomers, as well as due to the
challenges related to experimental studies thereof. Inter alia, this is especially true for viral fusion
proteins, which have been the focus of numerous studies for quite some time, but have provoked
unprecedented interest in view of the SARS-CoV-2 pandemic. However, despite numerous structurecentred
studies of the spike (S) protein effectuating target cell entry in coronaviruses, structural data
on the TMD as part of the entire spike protein are still incomplete, whereas this segment is known
to be crucial to the spike’s fusogenic activity. Therefore, in attempting to bring together currently
available data on the structure and dynamics of spike proteins’ TMDs, the present review aims to
tackle a highly pertinent task and contribute to a better understanding of the molecular mechanisms
underlying virus-mediated fusion, also offering a rationale for the design of novel efficacious methods
for the treatment of infectious diseases caused by SARS-CoV-2 and related viruses.

Keywords: молекулярное моделирование, molecular modelling, membrane protein structure, viral fusion protein, helix–helix interface, protein–protein interactions in membrane, transmembrane helical trimer, viral protein acylation, вирусный белок слияния, трансмембранный спиральный тример, белок–белковые взаимодействия в мембране, структура мембранного белка, ацилирование вирусного белка, интерфейс спираль–спираль