A crystallographic snapshot of tyrosine trans-phosphorylation in action

被引:53
作者
Chen, Huaibin [1 ]
Xu, Chong-Feng [1 ,2 ]
Ma, Jinghong [1 ]
Eliseenkova, Anna V. [1 ]
Li, Wanqing [3 ]
Pollock, Pamela M. [4 ]
Pitteloud, Nelly [5 ,6 ]
Miller, W. Todd [3 ]
Neubert, Thomas A. [1 ,2 ]
Mohammadi, Moosa [1 ]
机构
[1] NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA
[2] NYU, Sch Med, Skirball Inst, Kimmel Ctr Biol & Med, New York, NY 10016 USA
[3] SUNY Stony Brook, Sch Med, Dept Physiol & Biophys, Stony Brook, NY 11794 USA
[4] Translat Genom Res Inst, Canc & Cell Biol Div, Phoenix, AZ 85004 USA
[5] Massachusetts Gen Hosp, Harvard Ctr Reprod Endocrine Sci, Boston, MA 02114 USA
[6] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Boston, MA 02114 USA
基金
美国国家卫生研究院;
关键词
crystal structure; FGF receptor; RTKs;
D O I
10.1073/pnas.0807752105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Tyrosine trans-phosphorylation is a key event in receptor tyrosine kinase signaling, yet, the structural basis for this process has eluded definition. Here, we present the crystal structure of the FGF receptor 2 kinases caught in the act of trans-phosphorylation of Y769, the major C-terminal phosphorylation site. The structure reveals that enzyme- and substrate-acting kinases engage each other through elaborate and specific interactions not only in the immediate vicinity of Y769 and the enzyme active site, but also in regions that are as much of 18 angstrom away from D626, the catalytic base in the enzyme active site. These interactions lead to an unprecedented level of specificity and precision during the trans-phosphorylation on Y769. Time-resolved mass spectrometry analysis supports the observed mechanism of trans-phosphorylation. Our data provide a molecular framework for understanding the mechanism of action of Kallmann syndrome mutations and the order of trans-phosphorylation reactions in FGFRs. We propose that the salient mechanistic features of Y769 transphosphorylation are applicable to trans-phosphorylation of the equivalent major phosphorylation sites in many other RTKs.
引用
收藏
页码:19660 / 19665
页数:6
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