Dynamics of Membrane Proteins

Lall, Sahil; Mathew, M. K.

doi:10.1007/978-3-319-66601-3_10

Cited by 3 publications

(5 citation statements)

References 125 publications

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“…The other interface that we observe is a stretch of hydrophobic residues (LxxIVxxT) that extends throughout one face of the transmembrane helix. Such long hydrophobic stretches have previously been shown to stabilize transmembrane dimers (65,73,74). Apart from together participating in stabilizing the symmetric trimer, these two interfaces also associate in a different manner in our simulations, by forming an asymmetric trimer which we observe as the second most prominent ensemble in our simulations (Figure 2D).…”

Section: Discussionsupporting

confidence: 53%

“…The other interface extends throughout one face of the TM helix and is comprised of β-branched residues (LXXIVXXT). Similar sequences have been previously shown to stabilize TM dimerization (69,73,74). The trimeric spike TMD is stabilized by these two overlapping dimerization interfaces and an interplay between these two sequence motifs dictates the final conformations observed.…”

Section: Multiple Overlapping and Conflicting Dimerization Motifs Det...supporting

confidence: 62%

“…Dimerization of α-helices is frequently observed in natural membrane proteins and has been the system of choice to understand the self-association of both bitopic and multi-pass transmembrane domains (TMDs) (65). On the other hand, trimerization is primarily observed for β-barrel proteins on mitochondrial or prokaryotic membranes.…”

Section: Discussionmentioning

confidence: 99%

“…We could tease apart two overlapping dimerization interfaces that contribute to the trimerization of the spike transmembrane helix (Figure 4E). One of the two interfaces is the classical GxxxG stabilized right-handed dimer (54,55,65,70). This classical motif is overrepresented in the membrane helix sequence space and is probably the most well studied dimerizing interface (56,71,72).…”

Section: Discussionmentioning

confidence: 99%

“…7E) were very similar to those seen in the trimer simulations. One of these interfaces is formed by the well-studied GXXXG or GASright motif (52,55,69). This motif is overrepresented in the naturally occurring TM helix sequence space (70) and promotes TM helix dimerization through a combination of hydrogen bonding and van der Waals packing interactions (71,72).…”

Section: Multiple Overlapping and Conflicting Dimerization Motifs Det...mentioning

confidence: 99%

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Sequence of the SARS-CoV-2 spike transmembrane domain makes it inherently dynamic

Lall

Balaram

Gosavi

et al. 2021

Preprint

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The spike (S) protein is a trimeric, membrane-anchored fusion protein that enables coronaviruses, such as the SARS-CoV-2, to recognize and fuse with their hosts' cells. While the prefusion and postfusion structures of the ectomembrane domain of the spike protein are available, the corresponding organization of its transmembrane domain is obscure. Since the transmembrane and ectomembrane domains of fusion proteins are conformationally linked, an understanding of trimerization and transmembrane conformations in the viral envelope is a prerequisite to completely understand viral fusion by the spike protein. To address this, we computationally explored the self-assembly of the SARS-CoV-2 spike transmembrane domain, starting first by determining the membrane boundaries of the spike transmembrane helix. Using atomistic molecular dynamics simulations, we found the spike protein transmembrane domain to be plastic, and the transmembrane helix to be very dynamic. The observed movements of the helix changed the membrane embedded sequence, and thereby affected the conformational ensemble of the transmembrane assembly in Martini coarse grained simulations, even flipping the super-helical handedness. Analysis of the transmembrane organization of the spike transmembrane helix provided rich insights into the interfaces utilized to self-associate. Moreover, we identified two distinct cholesterol binding regions on the transmembrane helix with different affinities for the sterol. The cholesterol binding pockets overlapped with regions involved in the initiation of transmembrane protein-protein interaction. Together, the results from our multiscale simulations not only provide insight into understudied trimeric helical interfaces in biomembranes, but also enhance our understanding of the elusive transmembrane conformational dynamics of SARS-CoV-2 spike and more generally of viral fusion proteins. These insights should enable the inclusion of the conformations of the spike protein transmembrane domain into the prevalent models of virus fusion.

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Section: Discussionsupporting

confidence: 53%

Section: Multiple Overlapping and Conflicting Dimerization Motifs Det...supporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%