Ko, Sunggeon Ahn, Kyo-Eun Lee, Young-Min Ahn, Hee-Chul Lee, Weontae 2024-01-20T21:05:12Z 2024-01-20T21:05:12Z 2021-09-03 2009-06-26 0006-291X https://pubs.kist.re.kr/handle/201004/132383 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 beta-barrel with two beta-sheets comprised of five beta-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. (C) 2009 Elsevier Inc. All rights reserved. English ACADEMIC PRESS INC ELSEVIER SCIENCE SH2-KINASE LINKER NMR-SPECTROSCOPY SH3 DOMAIN BRK EXPRESSION PROGRAM FAMILY TUMORS Structural basis of the auto-inhibition mechanism of nonreceptor tyrosine kinase PTK6 Article 10.1016/j.bbrc.2009.04.103 1 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.384, no.2, pp.236 - 242 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 384 2 236 242 scie scopus 000266462500019 2-s2.0-65549103970 Biochemistry & Molecular Biology Biophysics Biochemistry & Molecular Biology Biophysics Article SH2-KINASE LINKER NMR-SPECTROSCOPY SH3 DOMAIN BRK EXPRESSION PROGRAM FAMILY TUMORS PTK6 Auto-regulation SH3 Intra-molecular interaction NMR spectroscopy