02400nas a2200181   4500008004100000245010500041210006900146260000800215300001100223490000900234520173200243100002501975700002402000700001702024700002602041700002002067856013102087       2017                        eng d00aRole of spatial inhomogenity in GPCR dimerisation predicted by receptor association-diffusion models0 aRole of spatial inhomogenity in GPCR dimerisation predicted by r  cJUN  a0360020 v14  3 aG protein-coupled receptor (GPCR) association is an emerging paradigm with far reaching implications in the regulation of signalling pathways and therapeutic interventions. Recent super resolution microscopy studies have revealed that receptor dimer steady state exhibits sub-second dynamics. In particular the GPCRs, muscarinic acetylcholine receptor M-1 (M1MR) and formyl peptide receptor (FPR), have been demonstrated to exhibit a fast association/dissociation kinetics, independent of ligand binding. In this work, we have developed a spatial kinetic Monte Carlo model to investigate receptor homo-dimerisation at a single receptor resolution. Experimentally measured association/dissociation kinetic parameters and diffusion coefficients were used as inputs to the model. To test the effect of membrane spatial heterogeneity on the simulated steady state, simulations were compared to experimental statistics of dimerisation. In the simplest case the receptors are assumed to be diffusing in a spatially homogeneous environment, while spatial heterogeneity is modelled to result from crowding, membrane micro-domains and cytoskeletal compartmentalisation or 'corrals'. We show that a simple association-diffusion model is sufficient to reproduce M1MR association statistics, but fails to reproduce FPR statistics despite comparable kinetic constants. A parameter sensitivity analysis is required to reproduce the association statistics of FPR. The model reveals the complex interplay between cytoskeletal components and their influence on receptor association kinetics within the features of the membrane landscape. These results constitute an important step towards understanding the factors modulating GPCR organisation.1 aDeshpande, Sneha, A.1 aPawar, Aiswarya, B.1 aDighe, Anish1 aAthale, Chaitanya, A.1 aSengupta, Durba  uhttps://library.ncl.res.in/content/role-spatial-inhomogenity-gpcr-dimerisation-predicted-receptor-association-diffusion-models01941nas a2200193   4500008004100000022001400041245008000055210006900135260000900204300001200213490000800225520126800233653003901501653003101540653002401571100002401595700002001619856010801639       2019                        eng d  a1047-847700aResolving the conformational dynamics of ErbB growth factor receptor dimers0 aResolving the conformational dynamics of ErbB growth factor rece  cAUG   a225-2330 v2073 a<p>The combinatorial dimerization of the ErbB growth factor receptors (ErbB(1) - ErbB(4)) are critical for their function. Here, we have characterized the conformational dynamics of ErbB transmembrane homo-dimers and hetero-dimers by using a coarse-grain simulation framework. All dimers, except ErbB (4-4) and ErbB(1-4), exhibit at least two conformations. The reported NMR structures correspond to one of these conformations, representing the N-terminal active state in ErbB(1-1) (RH2), ErbB(2-2) (RH1) and ErbB(4-4) (RH) homo-dimers and the LH dimer in ErbB(3-3) homo-dimer, validating the computational approach. Further, we predict a right-handed ErbB(4) dimer conformer that warrants experimental testing. The five hetero-dimers that have not yet been experimentally resolved display prominent right-handed dimers associating by the SmXXXSm motif. Our results provide insights into the constitutive signaling of ErbB(4) after cleavage of the extracellular region. The presence of the inactive-like dimer conformers leading to symmetric kinase domains gives clues on the autoinhibition of the receptor dimers. The dimer states characterized here represent an important step towards understanding the combinatorial cross associations in the ErbB family.</p>
10aMartini coarse-grained simulations10aMembrane protein structure10aTransmembrane dimer1 aPawar, Aiswarya, B.1 aSengupta, Durba  uhttps://library.ncl.res.in/content/resolving-conformational-dynamics-erbb-growth-factor-receptor-dimers02054nas a2200205   4500008004100000022001400041245009000055210006900145260000800214520132800222653001601550653003301566653001501599653002401614653003701638653001701675100002401692700002001716856011201736       2021                        eng d  a0022-263100aRole of cholesterol in transmembrane dimerization of the ErbB2 growth factor receptor0 aRole of cholesterol in transmembrane dimerization of the ErbB2 g  cJAN3 a<p>The association of ErbB2 growth factor receptors is critical for cell growth and potentiates tumor proliferation in several cancer types. An important aspect in ErbB2 association is the role of lipids such as cholesterol, especially since their metabolism is often reprogrammed in cancer cells. Here, we have coupled metadynamics with coarse-grain simulations to identify cholesterol effects in the transmembrane dimerization of ErbB2 receptors. Overall, cholesterol interactions are observed with the receptor that directly tunes the association energetics. Several dimer conformations are identified both in the presence and absence of cholesterol, although the dimer regime appears to be more favorable in the presence of cholesterol. We observe an overall modulation of the underlying energy profile and the symmetric active and inactive conformational states are not distinguished in the presence of cholesterol. We show that cholesterol binds to the receptor transmembrane domain at a site (CRAC motif) that overlaps with the dimer interface (SmXXXSm motif). The competition between the transmembrane interactions and cholesterol interactions decides the final conformational landscape. Our work is an important step toward characterizing cholesterol effects in ErbB2 membrane receptor function. [GRAPHICS] .</p>
10aCholesterol10aErbB2 growth factor receptor10aHer2 dimer10aJuxtamembrane dimer10aMartini coarse-grain simulations10aMetadynamics1 aPawar, Aiswarya, B.1 aSengupta, Durba  uhttps://library.ncl.res.in/content/role-cholesterol-transmembrane-dimerization-erbb2-growth-factor-receptor