Molecular aspects of the interaction between Mason—Pfizer monkey virus matrix protein and artificial phospholipid membrane

Abstract

The Mason-Pfizer monkey virus is a type D retrovirus, which assembles its immature particles in the cytoplasm prior to their transport to the host cell membrane. The association with the membrane is mediated by the N-terminally myristoylated matrix protein. To reveal the role of particular residues which are involved in the capsid-membrane interaction, covalent labelling of arginine, lysine and tyrosine residues of the Mason-Pfizer monkey virus matrix protein bound to artificial liposomes containing 95% of phosphatidylcholine and 5% phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P ) was performed. The experimental results were interpreted by multiscale molecular dynamics simulations. The application of these two complementary approaches helped us to reveal that matrix protein specifically recognizes the PI(4,5)P molecule by the residues K20, K25, K27, K74, and Y28, while the residues K92 and K93 stabilizes the matrix protein orientation on the membrane by the interaction with another PI(4,5)P molecule. Residues K33, K39, K54, Y66, Y67, and K87 appear to be involved in the matrix protein oligomerization. All arginine residues remained accessible during the interaction with liposomes which indicates that they neither contribute to the interaction with membrane nor are involved in protein oligomerization. Proteins 2016; 84:1717-1727. © 2016 Wiley Periodicals, Inc.

Differences and commonalities in plasma membrane recruitment of the two morphogenetically distinct retroviruses HIV-1 and MMTV

“…The lower affinity of the M-PMV MA, a D-type retrovirus, to liposomes has previously been observed by Kroupa et al (41), where only 5% of the M-PMV MA was bound to PI4,5P 2 -containing liposomes in contrast to more than 40% of the HIV-1 MA bound to the same liposomes. In our previous study, we found that ;50% of the M-PMV MA was bound to PI4,5P 2 -containing liposomes (39). However, the concentration of the phospholipids used in the mixture of M-PMV MA and liposomes was almost five times higher than that used by Kroupa et al (41) and twice as high as in our current study to obtain a sufficient amount of protein bound to the liposomes for subsequent mapping experiments.…”

“…Additionally, the comparison of HIV-1 and MMTV MA LBA results shows that the HIV-1 MA HBR is able to mediate stronger electrostatic interactions than the HBR of the MMTV MA because HIV-1 exhibits a higher affinity to the liposomes than the MMTV MA under the same experimental conditions. Moreover, the higher affinity of the HIV-1 MA to PI4,5P 2 -containing liposomes as compared with another B/D-type retrovirus, M-PMV, has been observed previously (39,41), although its HBR is located at the N terminus of the MA and comprises eight basic residues. Therefore, we suppose that the affinity of different MAs to PI4,5P 2 is related to the morphogenesis of particular retroviruses.…”

“…This can significantly affect their tendency of myristoyl release. In our previous study, we used multiscale MD simulations to describe the MA-membrane interaction of M-PMV, which is morphogenetically similar to MMTV, and the release of myristoyl was not observed during the simulations, although the M-PMV MA stably interacted with the membrane by its HBR bound to PI4,5P 2 molecules (39). Additionally, the exposure of myristoyl was not observed in the case of HIV-2 MA under any of the conditions ensuring the exposure of the myristoyl of the HIV-1 MA (37).…”

“…Although the release of virus-like HIV-2 particles is PI4,5P 2 -dependent as in HIV-1, the trimerization of the HIV-2 MA and its interaction with PI4,5P 2 does not trigger the myristoyl exposure (37). Similarly, the myristoyl exposure was not observed in the case of the M-PMV MA when it interacted with truncated PI4,5P 2 (38) or during the CG-MD simulations of the M-PMV MA interaction with the lipid bilayer (39). Nevertheless, the tendency of the nonmyristoylated M-PMV MA to form trimers in contrast to its myristoylated form suggests that the exposure of myristoyl does occur and that it induces a conformational change of M-PMV MA, which favors trimerization (40).…”

“…We have used a combination of the MS-based protein surface mapping method and CG-MD simulations. This approach has already been utilized to describe M-PMV MA-membrane interaction (39). Additionally, we have applied surface mapping to broaden our knowledge of the HIV-1 MA interaction with the membrane.…”