1wa7
From Proteopedia
SH3 DOMAIN OF HUMAN LYN TYROSINE KINASE IN COMPLEX WITH A HERPESVIRAL LIGAND
Structural highlights
Function[TIP_SHV2C] Plays a critical role in virus induced T-cell transformation. Binds to T-cell-specific tyrosine kinase LCK SH2 and SH3 domains, thereby activating its kinase activity. Once phosphorylated by host LCK, forms a complex with at least STAT 1 and 3, resulting on the phosphorylation of STAT3 and presumably STAT1, and their migration into the nucleus to induce transcription of target genes. Stimulates host ILF3/NF-AT-90 activity. Association with host NXF1/TAP transduces the signal up-regulating surface expression of adhesion molecules as well as activating NF-kappa-B activity. Acts synergistically with StpC to stimulate NF-kappa-B activity and interleukin-2 gene expression. Activation of NF-kappa-B protects lymphocytes from apoptosis, thereby facilitating viral induced cell transformation. May cause down-regulation of host LCK and cell apoptosis when stably overexpressed ex vivo. Interaction with WDR48 induce degradation of T-cell receptor in a lysosome-dependent fashion, when both proteins are overexpressed. The biological effect of this interaction remains controversial since no T-cell receptor degradation is observed in infected cells. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedHerpesvirus saimiri codes for a tyrosine kinase interacting protein (Tip) that interacts with both the SH3 domain and the kinase domain of the T-cell-specific tyrosine kinase Lck via two separate motifs. The activation of Lck by Tip is considered as a key event in the transformation of human T-lymphocytes during herpesviral infection. We investigated the interaction of proline-rich Tip peptides with the LckSH3 domain starting with the structural characterization of the unbound interaction partners. The solution structure of the LckSH3 was determined by heteronuclear multidimensional nuclear magnetic resonance (NMR) spectroscopy using 44 residual dipolar couplings in addition to the conventional experimental restraints. Circular dichroism spectroscopy proved that the polyproline helix of Tip is already formed prior to SH3 binding and is conformationally stable. NMR titration experiments point out three major regions of the Tip-Lck interaction comprising the RT loop, the n-src loop, and a helical turn preceding the last strand of the beta-sheet. Further changes of the chemical shifts were observed for the N- and C-terminal beta-strands of the SH3 domain, indicating additional contacts outside the proline-rich segment or subtle structural rearrangements transmitted from the binding site of the proline helix. Fluorescence spectroscopy shows that Tip binds to the SH3 domains of several Src kinases (Lck, Hck, Lyn, Src, Fyn, Yes), exhibiting the highest affinities for Lyn, Hck, and Lck. Structural investigation of the binding of a herpesviral protein to the SH3 domain of tyrosine kinase Lck.,Schweimer K, Hoffmann S, Bauer F, Friedrich U, Kardinal C, Feller SM, Biesinger B, Sticht H Biochemistry. 2002 Apr 23;41(16):5120-30. PMID:11955060[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Herpesvirus saimiri | Human | Transferase | Bauer, F | Hoffmann, S | Roesch, P | Schweimer, K | Sticht, H | Hypothetical protein | Ligand | Lyn | Proto-oncogene | Sh3 domain | Signal transduction | Tip | Tyrosine kinase
