Force-induced unfolding simulations of the human Notch1 negative negulatory negion: Possible roles of the heterodimerization domain in mechanosensing

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dc.contributor.author Chen, Jianhan
dc.contributor.author Zolkiewska, Anna
dc.date.accessioned 2011-10-13T16:24:14Z
dc.date.available 2011-10-13T16:24:14Z
dc.date.issued 2011-10-13
dc.identifier.uri http://hdl.handle.net/2097/12373
dc.description.abstract Notch receptors are core components of the Notch signaling pathway and play a central role in cell fate decisions during development as well as tissue homeostasis. Upon ligand binding, Notch is sequentially cleaved at the S2 site by an ADAM protease and at the S3 site by the c-secretase complex. Recent X-ray structures of the negative regulatory region (NRR) of the Notch receptor reveal an auto-inhibited fold where three protective Lin12/Notch repeats (LNR) of the NRR shield the S2 cleavage site housed in the heterodimerization (HD) domain. One of the models explaining how ligand binding drives the NRR conformation from a protease-resistant state to a protease-sensitive one invokes a mechanical force exerted on the NRR upon ligand endocytosis. Here, we combined physics-based atomistic simulations and topology-based coarse-grained modeling to investigate the intrinsic and force-induced folding and unfolding mechanisms of the human Notch1 NRR. The simulations support that external force applied to the termini of the NRR disengages the LNR modules from the heterodimerization (HD) domain in a well-defined, largely sequential manner. Importantly, the mechanical force can further drive local unfolding of the HD domain in a functionally relevant fashion that would provide full proteolytic access to the S2 site prior to heterodimer disassociation. We further analyzed local structural features, intrinsic folding free energy surfaces, and correlated motions of the HD domain. The results are consistent with a model in which the HD domain possesses inherent mechanosensing characteristics that could be utilized during Notch activation. This potential role of the HD domain in ligand-dependent Notch activation may have implications for understanding normal and aberrant Notch signaling. en_US
dc.relation.uri www.plosone.org en_US
dc.subject Notch1 en_US
dc.subject Notch signaling en_US
dc.subject Inter-cellular communication pathways en_US
dc.subject Embryonic development en_US
dc.subject Tissue homeostasis en_US
dc.title Force-induced unfolding simulations of the human Notch1 negative negulatory negion: Possible roles of the heterodimerization domain in mechanosensing en_US
dc.type Article (publisher version) en_US
dc.date.published 2011 en_US
dc.citation.doi doi:10.1371/journal.pone.0022837 en_US
dc.citation.issue 7 en_US
dc.citation.jtitle PLoS ONE en_US
dc.citation.spage e22837 en_US
dc.citation.volume 6 en_US
dc.contributor.authoreid jianhanc en_US
dc.contributor.authoreid zolkiea en_US

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