期刊
BIOCHEMISTRY
卷 57, 期 35, 页码 5257-5269出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.8b00677
关键词
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资金
- GRF [14304915, 14321116]
- HMRF [15140052, AoE/M-09/12]
- National Natural Science Foundation of China [21628201]
- Canadian Institute of Health Researh grant
Discerning the different interaction states during dynamic protein ligand binding is difficult. Here we apply site specific cysteine-alpha-chloroacetyl cross-linking to scrutinize the binding between the Src homology 2 (SH2) domain and phosphotyrosine (pY) peptides, a highly dynamic interaction that is a key to cellular signal transduction. From a model SH2 protein to a set of representative SH2 domains, we showed here that a proximity-induced cysteine-alpha-chloroacetyl reaction cross linked two spatially adjacent chemical groups as a result of the binding interaction, and reciprocally, the information about the interaction states can be deduced from the cross-linked products. To our surprise, we found SH2 domains can adopt a reverse binding mode with single-pronged, two-pronged, and half' pY peptides. This finding was further supported by a set of 500 ns molecular dynamics simulations. This serendipitous finding defies the canonical theory of SH2 binding, suggests a possible answer about the source of the versatility of SH2 signaling, and sets a model for other protein binding interactions.
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