2rsy
From Proteopedia
Solution structure of the SH2 domain of Csk in complex with a phosphopeptide from Cbp
Structural highlights
Function[CSK_RAT] Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK (By similarity).[1] [2] [PHAG1_RAT] Negatively regulates TCR (T-cell antigen receptor)-mediated signaling in T-cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Promotes CSK activation and recruitment to lipid rafts, which results in LCK inhibition. Inhibits immunological synapse formation by preventing dynamic arrangement of lipid raft proteins. May be involved in cell adhesion signaling.[3] [4] [5] Publication Abstract from PubMedProteins with Src homology 2 (SH2) domains play major roles in tyrosine kinase signaling. Structures of many SH2 domains have been studied, and the regions involved in their interactions with ligands have been elucidated. However, these analyses have been performed using short peptides consisting of phosphotyrosine followed by a few amino acids, which are described as the canonical recognition sites. Here, we report the solution structure of the SH2 domain of C-terminal Src kinase (Csk) in complex with a longer phosphopeptide from the Csk-binding protein (Cbp). This structure, together with biochemical experiments, revealed the existence of a novel binding region in addition to the canonical phosphotyrosine 314-binding site of Cbp. Mutational analysis of this second region in cells showed that both canonical and novel binding sites are required for tumor suppression through the Cbp-Csk interaction. Furthermore, the data indicate an allosteric connection between Cbp binding and Csk activation that arises from residues in the betaB/betaC loop of the SH2 domain. Identification of a new interaction mode between the Src homology 2 domain of C-terminal Src kinase (Csk) and Csk-binding protein/phosphoprotein associated with glycosphingolipid microdomains.,Tanaka H, Akagi K, Oneyama C, Tanaka M, Sasaki Y, Kanou T, Lee YH, Yokogawa D, Dobenecker MW, Nakagawa A, Okada M, Ikegami T J Biol Chem. 2013 May 24;288(21):15240-54. doi: 10.1074/jbc.M112.439075. Epub, 2013 Apr 2. PMID:23548896[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Buffalo rat | Large Structures | Non-specific protein-tyrosine kinase | Akagi, K | Debenecker, M | Ikegami, T | Kanou, T | Lee, Y | Nakagawa, A | Okada, M | Oneyama, C | Sasaki, Y | Tanaka, H | Tanaka, M | Yokogawa, D | Cbp | Csk | Sh2 domain | Solution structure | Transferase-signaling protein complex
