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J. Biol. Chem., Vol. 279, Issue 6, 4962-4969, February 6, 2004

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Structural Basis for the Specific Recognition of RET by the Dok1 Phosphotyrosine Binding Domain^*

Ning Shi, Sheng Ye, Mark Bartlam, Maojun Yang, Jing Wu, Yiwei Liu, Fei Sun, Xueqing Han, Xiaozhong Peng, Boqing Qiang, Jiangang Yuan¶, and Zihe Rao||

From the Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100084 and the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, National Human Genome Center, Beijing 100005, China

Dok1 is a common substrate of activated protein-tyrosine kinases. It is rapidly tyrosine-phosphorylated in response to receptor tyrosine activation and interacts with ras GTPase-activating protein and Nck, leading to inhibition of ras signaling pathway activation and the c-Jun N-terminal kinase (JNK) and c-Jun activation, respectively. In chronic myelogenous leukemia cells, it has shown constitutive phosphorylation. The N-terminal phosphotyrosine binding (PTB) domain of Dok1 can recognize and bind specifically to phosphotyrosine-containing motifs of receptors. Here we report the crystal structure of the Dok1 PTB domain alone and in complex with a phosphopeptide derived from RET receptor tyrosine kinase. The structure consists of a -sandwich composed of two nearly orthogonal, 7-stranded, antiparallel -sheets, and it is capped at one side by a C-terminal -helix. The RET phosphopeptide binds to Dok1 via a surface groove formed between strand 5 and the C-terminal -helix of the PTB domain. The structures reveal the molecular basis for the specific recognition of RET by the Dok1 PTB domain. We also show that Dok1 does not recognize peptide sequences from TrkA and IL-4, which are recognized by Shc and IRS1, respectively.

Received for publication, October 7, 2003 , and in revised form, November 5, 2003.

The atomic coordinates and structure factors (code 1P5T) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Sciences Foundation of China (Grants 30200045 and 30221003); the National Program for Key Basic Research Project ("973" Grants G1999075602 and G1999011902); and the National High Technology Research and Development Program ("863" Grant 2002BA711A12). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence may be addressed. Tel.: 86-10-65296411; Fax: 86-10-65240529; E-mail: yuanjiangang{at}pumc.edu.cn.

^|| To whom correspondence may be addressed: Laboratory of Structural Biology, School of Life Science and Engineering, Tsinghua University, Beijing 100084, P. R. China. Tel.: 86-10-6277-1493; Fax: 86-10-6277-3145; E-mail: raozh{at}xtal.tsinghua.edu.cn.

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