Structural basis of the auto-inhibition mechanism of nonreceptor tyrosine kinase PTK6

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• 作者：Sunggeon Ko ; Kyo-Eun Ahn ; Young-Min Lee ; Hee-Chul Ahn ; Weontae Lee
• 关键词：PTK6 ; Auto-regulation ; SH3 ; Intra-molecular interaction ; NMR spectroscopy
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2009
• 出版时间：26 June 2009
• 年：2009
• 卷：384
• 期：2
• 页码：236-242
• 全文大小：1919 K

文摘

Protein tyrosine kinase 6 (PTK6) is composed of SH3, SH2, and Kinase domains, with a linker region (Linker) between the SH2 and Kinase domains. Here, we report the structural basis of the SH3–Linker interaction that results in auto-inhibition of PTK6. The solution structures of the SH3 domain and SH3/Linker complex were determined by NMR spectroscopy. The structure of the SH3 domain forms a conventional β-barrel with two β-sheets comprised of five β-strands. However, the molecular topology and charge distribution of PTK6-SH3 slightly differs from that of the other SH3 domains. The structure of the N-terminal Linker within the complex showed that the proline-rich region (P175–P187) of the Linker forms a compact hairpin structure through hydrophobic interactions. The structure of the SH3/Linker complex revealed intra-molecular interaction between the amino acid pairs R22/E190, W44/W184, N65/P177, and Y66/P179. Mutations in PTK6 at R22, W44, N65, and Y66 residues in the SH3 domain increased catalytic activity compared with wild-type protein, implying that specific interactions between hydrophobic residues in the proline-rich linker region and hydrophobic residues in the SH3 domain are mainly responsible for down-regulating the catalytic activity of PTK6.