4JE4

Crystal Structure of Monobody NSa1/SHP2 N-SH2 Domain Complex

4JE4 の概要

• エントリーDOI: 10.2210/pdb4je4/pdb
• 関連するPDBエントリー: 4JEG
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11, Monobody NSa1 (3 entities in total)
• 機能のキーワード: engineered binding protein, shp2 sh2-monobody complex, phosphatase, phosphotyrosine binding, phosphorylation, signaling protein-protein binding complex, signaling protein/protein binding
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm: Q06124
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22233.82

構造登録者

Sha, F.,Koide, S. (登録日: 2013-02-26, 公開日: 2013-08-28, 最終更新日: 2024-02-28)

主引用文献

Sha, F.,Gencer, E.B.,Georgeon, S.,Koide, A.,Yasui, N.,Koide, S.,Hantschel, O.
Dissection of the BCR-ABL signaling network using highly specific monobody inhibitors to the SHP2 SH2 domains.
Proc.Natl.Acad.Sci.USA, 110:14924-14929, 2013

PubMed Abstract: The dysregulated tyrosine kinase BCR-ABL causes chronic myelogenous leukemia in humans and forms a large multiprotein complex that includes the Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2). The expression of SHP2 is necessary for BCR-ABL-dependent oncogenic transformation, but the precise signaling mechanisms of SHP2 are not well understood. We have developed binding proteins, termed monobodies, for the N- and C-terminal SH2 domains of SHP2. Intracellular expression followed by interactome analysis showed that the monobodies are essentially monospecific to SHP2. Two crystal structures revealed that the monobodies occupy the phosphopeptide-binding sites of the SH2 domains and thus can serve as competitors of SH2-phosphotyrosine interactions. Surprisingly, the segments of both monobodies that bind to the peptide-binding grooves run in the opposite direction to that of canonical phosphotyrosine peptides, which may contribute to their exquisite specificity. When expressed in cells, monobodies targeting the N-SH2 domain disrupted the interaction of SHP2 with its upstream activator, the Grb2-associated binder 2 adaptor protein, suggesting decoupling of SHP2 from the BCR-ABL protein complex. Inhibition of either N-SH2 or C-SH2 was sufficient to inhibit two tyrosine phosphorylation events that are critical for SHP2 catalytic activity and to block ERK activation. In contrast, targeting the N-SH2 or C-SH2 revealed distinct roles of the two SH2 domains in downstream signaling, such as the phosphorylation of paxillin and signal transducer and activator of transcription 5. Our results delineate a hierarchy of function for the SH2 domains of SHP2 and validate monobodies as potent and specific antagonists of protein-protein interactions in cancer cells.

PubMed: 23980151
DOI: 10.1073/pnas.1303640110

実験手法

X-RAY DIFFRACTION (2.31 Å)