01941nas 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-dimers02311nas a2200241   4500008004100000022001400041245008800055210006900143260000800212300001100220490000800231520148500239653001601724653001801740653003901758653003101797653003001828100002501858700002401883700002601907700002001933856011601953       2020                        eng d  a0009-308400aLipid-dependent conformational landscape of the ErbB2 growth factor receptor dimers0 aLipiddependent conformational landscape of the ErbB2 growth fact  cAUG  a1049110 v2303 a<p>Altered lipid metabolism has been linked to cancer development and progression. Several roles have been attributed to the increased saturation and length of lipid acyl tails observed in tumors, but its effect on signaling receptors is still emerging. In this work, we have analyzed the lipid dependence of the ErbB2 growth factor receptor dimerization that plays an important role in the pathogenesis of breast cancer. We have performed coarse-grain ensemble molecular dynamics simulations to comprehensively sample the ErbB2 monomer-dimer association. Our results indicate a dynamic dimer state with a complex conformational landscape that is modulated with increasing lipid tail length. We resolve the native N-terminal ``active'' and C-terminal ``inactive'' conformations in all membrane compositions. However, the relative population of the N-terminal and C-terminal conformers is dependent on length of the saturated lipid tails. In short-tail membranes, additional non-specific dimers are observed which are reduced or absent in long-tailed bilayers. Our results indicate that the relative population as well as the structure of the dimer state is modulated by membrane composition. We have correlated these differences to local perturbations of the membrane around the receptor. Our work is an important step in characterizing ErbB dimers in healthy and diseased states and emphasize the importance of sampling lipid dynamics in understanding receptor association.</p>
10aErbB2 dimer10aLipid effects10aMartini coarse-grained simulations10aMembrane protein structure10aTransmembrane association1 aGopal, Srinivasa, M.1 aPawar, Aiswarya, B.1 aWassenaar, Tsjerk, A.1 aSengupta, Durba  uhttps://library.ncl.res.in/content/lipid-dependent-conformational-landscape-erbb2-growth-factor-receptor-dimers