2IIM

SH3 Domain of Human Lck

2IIM の概要

• エントリーDOI: 10.2210/pdb2iim/pdb
• 関連するPDBエントリー: 1LCK
• 分子名称: Proto-oncogene tyrosine-protein kinase LCK, ZINC ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: beta-barrels, signaling protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P06239
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 7194.29

構造登録者

Romir, J.,Egerer-Sieber, C.,Muller, Y.A. (登録日: 2006-09-28, 公開日: 2006-11-07, 最終更新日: 2023-08-30)

主引用文献

Romir, J.,Lilie, H.,Egerer-Sieber, C.,Bauer, F.,Sticht, H.,Muller, Y.A.
Crystal structure analysis and solution studies of human Lck-SH3; zinc-induced homodimerization competes with the binding of proline-rich motifs.
J.Mol.Biol., 365:1417-1428, 2007

PubMed Abstract: In cytosolic Src-type tyrosine kinases the Src-type homology 3 (SH3) domain binds to an internal proline-rich motif and the presence or the absence of this interaction modulates the kinase enzymatic activity. The Src-type kinase Lck plays an important role during T-cell activation and development, since it phosphorylates the T-cell antigen receptor in an early step of the activation pathway. We have determined the crystal structure of the SH3 domain from Lck kinase at a near-atomic resolution of 1.0 A. Unexpectedly, the Lck-SH3 domain forms a symmetrical homodimer in the crystal and the dimer comprises two identical zinc-binding sites in the interface. The atomic interactions formed across the dimer interface resemble strikingly those observed between SH3 domains and their canonical proline-rich ligands, since almost identical residues participate in both contacts. Ultracentrifugation experiments confirm that in the presence of zinc ions, the Lck-SH3 domain also forms dimers in solution. The Zn(2+) dissociation constant from the Lck-SH3 dimer is estimated to be lower than 100 nM. Moreover, upon addition of a proline-rich peptide with a sequence corresponding to the recognition segment of the herpesviral regulatory protein Tip, competition between zinc-induced homodimerization and binding of the peptide can be detected by both fluorescence spectroscopy and analytical ultracentrifugation. These results suggest that in vivo, too, competition between Lck-SH3 homodimerization and binding of regulatory proline-rich sequence motifs possibly represents a novel mechanism by which kinase activity is modulated. Because the residues that form the zinc-binding site are highly conserved among Lck orthologues but not in other Src-type kinases, the mechanism might be peculiar to Lck and to its role in the initial steps of T-cell activation.

PubMed: 17118402
DOI: 10.1016/j.jmb.2006.10.058

実験手法

X-RAY DIFFRACTION (1 Å)