报告题目：

Mechanism of mechanical regulated Notch activation and structural bases of Notch NRR related T-ALL

报告人:                Jizhong Lou 研究员

Laboratory of non-coding RNAs, Institute of Biophysics, Chinese Academy of Sciences      

时间：2014年1月21日(周二)  15:00                 

地点：中国科学院力学研究所344会议室

报告摘要：

Notch proteins are transmembrane receptors which can transduce signals between cells. Upon binding to their ligands on the neighboring cells, notch receptors can be activated and undergo conformational changes which enable their proteolysis by ADAM-family of metalloproteases. The cleavage site of notch protein located on its hetrodimerizaton domain (HD) of the negative regulatory region (NRR) proximal to the N-terminal of the transmembrane helix.  Recent crystal structures on several notch proteins indicated that a series of three Lin12/Notch repeats (LNRs) wrap around the HD and bury the cleavage site to prevent it from proteolysis at the normal conditions without ligand binding. Studies indicated that notch/ligand binding may also induce internalization of the transmembrane ligand and it is hypothesized that the mechanical force generated by the ligand internalization is the key factor to activate the Notch for cleavage but the detail process remains poorly understand.

Using steered molecular dynamics simulations, we confirmed that mechanical force can unwrap the LNRs sequentially from the HD and finally expose the cleavage site. Two possible force-activation pathways are observed, differed with the order of unwrapping of the third LNR and the unfolding of the HD. On the other hand, several gain-of-function mutations on the HD have been identified in patients with T cell acute lymphoblastic leukemia/lymphoma (T-ALL). Our simulations on the force-induced activation of these mutant NRRs show that the mutations alter the force-requirements on either the unwrapping or the unfolding processes, which results in enhanced exposure of the cleavage site and leads to easier proteolysis. These results imply possible mechanisms of T-ALL related from the extracellular domain of notch and provide potential therapeutic drug target.