期刊
STRUCTURE
卷 19, 期 4, 页码 546-554出版社
CELL PRESS
DOI: 10.1016/j.str.2011.01.016
关键词
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资金
- NIH (National Institutes of Health) [R01 CA092433, P01 119070, R01 070590, R01 086507]
- Leukemia and Lymphoma Society
- Cancer Research Institute
- Waters
Notch proteins are transmembrane receptors that normally adopt a resting state poised to undergo activating proteolysis upon ligand engagement. Receptor quiescence is maintained by three LIN12/Notch repeats (LNRs), which wrap around a heterodimerization domain (HD) divided by furin cleavage at site Si during maturation. Ligand binding initiates signaling by inducing sensitivity of the HD to proteolysis at the regulated S2 cleavage site. Here, we used hydrogen exchange mass spectrometry to examine the solution dynamics of the Notch1 negative regulatory region in autoinhibited states before and after Si cleavage, in a proteolytically sensitive on state, and in a complex with an inhibitory antibody. Conversion to the on state leads to accelerated deuteration in the S2 region and in nearby secondary structural elements within the HD. In contrast, complexation with the inhibitory antibody retards deuteration around the S2 site. Together, these studies reveal how S2 site exposure is promoted by receptor activation and suppressed by inhibitory antibodies.
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