01364nas a2200145 4500008004100000245008900041210006900130260000800199490000700207520082400214100002001038700002001058700002001078856012001098 2019 eng d00aActin cytoskeleton and membrane interactions: role in GPCR function and organization0 aActin cytoskeleton and membrane interactions role in GPCR functi cSEP0 v853 a

Cell signaling networks are generally initiated at the cell membrane and mediated by receptors such as the G proteincoupled receptors (GPCRs). Adjacent to the cell membrane lies a complex network of proteins - the actin cytoskeleton to which several structural and physiological roles have been attributed. An emerging role of the cytoskeleton is to modulate GPCR function and organization, either directly or indirectly. The GPCR-cytoskeleton cross-talk is a complex hierarchical process where each step has its own set of rules and combinations. Due to the inherent complexity involved at each step and the multiple spatio-temporal levels, a complete picture is yet to emerge. In this review article, we provide an overview of actin-membrane interactions and how they modulate GPCR function and organization.

1 aPrakash, Shikha1 aKrishna, Anjali1 aSengupta, Durba uhttps://library.ncl.res.in/content/actin-cytoskeleton-and-membrane-interactions-role-gpcr-function-and-organization01972nas a2200157 4500008004100000022001400041245009100055210006900146260000900215300001000224490000800234520141000242100002001652700002001672856012201692 2019 eng d a0006-349500aInterplay between membrane curvature and cholesterol: role of palmitoylated caveolin-10 aInterplay between membrane curvature and cholesterol role of pal cJAN  a69-780 v1163 a

Caveolin-1 (cav-1) is an important player in cell signaling and endocytosis that has been shown to colocalize with cholesterol-rich membrane domains. Experimental studies with varying cav-1 constructs have suggested that it can induce both cholesterol clustering and membrane curvature. Here, we probe the molecular origin of membrane curvature and cholesterol clustering by cav-1 by using coarse-grain molecular dynamics simulations. We have performed a series of simulations of a functionally important cav-1 construct, comprising the membrane-interacting domains and a C-terminal palmitoyl tail. Our results suggest that cav-1 is able to induce cholesterol clustering in the membrane leaflet to which it is bound as well as the opposing leaflet. A positive membrane curvature is observed upon cav-1 binding in cholesterol-containing bilayers. Interestingly, we observe an interplay between cholesterol clustering and membrane curvature such that cav-1 is able to induce higher membrane curvature in cholesterol-rich membranes. The role of the cav-1 palmitoyl tail is less clear and appears to increase the membrane contacts. Further, we address the importance of the secondary structure of cav-1 domains and show that it could play an important role in membrane curvature and cholesterol clustering. Our work is an important step toward a molecular picture of caveolae and vesicular endocytosis.

1 aKrishna, Anjali1 aSengupta, Durba uhttps://library.ncl.res.in/content/interplay-between-membrane-curvature-and-cholesterol-role-palmitoylated-caveolin-102092nas a2200169 4500008004100000022001400041245020500055210006900260260000800329300001400337490000800351520137100359100002001730700002001750700002001770856013201790 2020 eng d a1520-610600aSphingomyelin effects in caveolin-1 mediated membrane curvature published as part of the journal of physical chemistry virtual special issue ``computational and experimental advances in biomembranes''0 aSphingomyelin effects in caveolin1 mediated membrane curvature p cJUN a5177-51850 v1243 a

The caveolin-1 (cav-1) protein is an integral component of caveolae and has been reported to colocalize with cholesterol and sphingomyelin-rich curved membrane domains. Here, we analyze the molecular interactions between cav-1 and sphingomyelin containing bilayers using a series of coarse-grain simulations, focusing on lipid clustering and membrane curvature. We considered a palmitoylated-cav-1 construct interacting with phospholipid/cholesterol membranes with asymmetrically distributed sphingomyelin, varying between 5 and 15% in total. We observe that cav-1 binds to the intracellular leaflet and induces a small positive curvature in the leaflet to which it is bound and an opposing negative curvature in the extracellular leaflet. Both cholesterol and sphingomyelin are observed to cluster in cav-1 bound membranes, mainly in the extracellular leaflet. Due to their negative spontaneous curvature, clustering of cholesterol and sphingomyelin facilitates membrane curvature such that the extent of either cholesterol or sphingomyelin clustering is dependent on the curvature induced. Our results suggest that cav-1 binding induces concentration-dependent curvature effects in sphingomyelin-rich membranes. Overall, our work is an important step in understanding the molecular basis of curvature and lipid clustering in cav1 bound cellular membranes.

1 aKrishna, Anjali1 aPrakash, Shikha1 aSengupta, Durba uhttps://library.ncl.res.in/content/sphingomyelin-effects-caveolin-1-mediated-membrane-curvature-published-part-journal-physical02094nas a2200169 4500008004100000022001400041245009000055210006900145260000800214300001200222490000800234520150600242100002001748700002001768700002001788856011601808 2021 eng d a1359-664000aCaveolin induced membrane curvature and lipid clustering: two sides of the same coin?0 aCaveolin induced membrane curvature and lipid clustering two sid cDEC a218-2350 v2323 aCaveolin-1 (cav-1) is a multi-domain membrane protein that is a key player in cell signaling, endocytosis and mechanoprotection. It is the principle component of cholesterol-rich caveolar domains and has been reported to induce membrane curvature. The molecular mechanisms underlying the interactions of cav-1 with complex membranes, leading to modulation of membrane topology and the formation of cholesterol-rich domains, remain elusive. In this study, we aim to understand the effect of lipid composition by analyzing the interactions of cav-1 with complex membrane bilayers comprised of about sixty lipid types. We have performed a series of coarse-grain molecular dynamics simulations using the Martini force-field with a cav-1 protein construct (residue 82-136) that includes the membrane binding domains and a palmitoyl tail. We observe that cav-1 induces curvature in this complex membrane, though it is restricted to a nanometer length scale. Concurrently, we observe a clustering of cholesterol, sphingolipids and other lipid molecules leading to the formation of nanodomains. Direct microsecond timescale interactions are observed for specific lipids such as cholesterol, phosphatidylserine and phosphatidylethanolamine lipid types. The results indicate that there is an interplay between membrane topology and lipid species. Our work is a step toward understanding how lipid composition and organization regulate the formation of caveolae, in the context of endocytosis and cell signaling.1 aPrakash, Shikha1 aKrishna, Anjali1 aSengupta, Durba uhttps://library.ncl.res.in/content/caveolin-induced-membrane-curvature-and-lipid-clustering-two-sides-same-coin00559nas a2200157 4500008004100000022001400041245008000055210006900135260000900204300001400213490000800227100002000235700002000255700002000275856010600295 2021 eng d a0006-349500aCaveolin mediated curvature and clustering: from simple to complex membrane0 aCaveolin mediated curvature and clustering from simple to comple cFEB  a232A-233A0 v1201 aPrakash, Shikha1 aKrishna, Anjali1 aSengupta, Durba uhttps://library.ncl.res.in/content/caveolin-mediated-curvature-and-clustering-simple-complex-membrane01829nas a2200217 4500008004100000022001400041245009100055210006900146260000900215490000700224520105300231653002101284653002101305653003701326653003501363653003101398100002001429700002001449700002001469856012201489 2023 eng d a1439-423500aCofilin-membrane interactions: electrostatic effects in phosphoinositide lipid binding0 aCofilinmembrane interactions electrostatic effects in phosphoino cFEB 0 v243 a

The actin cytoskeleton interacts with the cell membrane primarily through the indirect interactions of actin-binding proteins such as cofilin-1. The molecular mechanisms underlying the specific interactions of cofilin-1 with membrane lipids are still unclear. Here, we performed coarse-grain molecular dynamics simulations of cofilin-1 with complex lipid bilayers to analyze the specificity of protein-lipid interactions. We observed the maximal interactions with phosphoinositide (PIP) lipids, especially PIP2 and PIP3 lipids. A good match was observed between the residues predicted to interact and previous experimental studies. The clustering of PIP lipids around the membrane bound protein leads to an overall lipid demixing and gives rise to persistent membrane curvature. Further, through a series of control simulations, we observe that both electrostatics and geometry are critical for specificity of lipid binding. Our current study is a step towards understanding the physico-chemical basis of cofilin-PIP lipid interactions.

10acomplex membrane10alipid clustering10aMartini coarse-grain simulations10aMolecular dynamics simulations10aProtein-lipid interactions1 aPrakash, Shikha1 aKrishna, Anjali1 aSengupta, Durba uhttps://library.ncl.res.in/content/cofilin-membrane-interactions-electrostatic-effects-phosphoinositide-lipid-binding