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首页> 外文期刊>Biochemistry >Controlling the Activity of the Tec Kinase Itk by Mutation of the Phenylalanine Gatekeeper Residue
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Controlling the Activity of the Tec Kinase Itk by Mutation of the Phenylalanine Gatekeeper Residue

机译：通过苯丙氨酸关守残基的突变控制Tec激酶Itk的活性。

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摘要

The regulatory spine is a set of conserved residues that are assembled and disassembled uponnactivation and inactivation of kinases.We recently identified the regulatory spine within the immunologicallynimportant Tec family kinases and have shown that in addition to the core spine residues within the kinasendomain itself, contributions from the SH2-kinase linker region result in an extended spine structure for thisnkinase family. Disruption of the regulatory spine, either by mutation or by removal of the amino-terminalnSH2-kinase linker region or bymutation of core spine residues, leads to inactivation of the Tec kinases.Withna focus on the Tec familymembers, Itk and Btk, we now show that the gatekeeper residue is also critical for thenassembly of the regulatory spine. Mutation of the bulky Itk F434 gatekeeper residue to alanine or glycineninactivates Itk. The activity of the Itk F434Amutant can be recovered by a secondary sitemutation within thenN-terminal lobe, specifically L432I. The Itk L432I mutation likely rescues the activity of the gatekeepernF434A mutation by promoting the assembly of the regulatory spine. We also show that mutation of the Itknand Btk gatekeeper residues to methionine is sufficient to activate the isolated kinase domains of Tec kinasesnin the absence of the amino-terminal SH2-kinase linker. Thus, shifting the conformational equilibriumnbetween the assembled and disassembled states of the regulatory spine by changing the nature of thengatekeeper residue is key to regulating the activity of Tec kinases.
机译：调节脊柱是一组保守的残基，在激酶失活和失活后会组装和分解。我们最近在免疫学上很重要的Tec家族激酶中发现了调节脊柱，并且表明除了激酶结构域本身的核心脊柱残基外， SH2-激酶接头区域导致该激酶家族的脊柱结构扩展。通过突变或通过去除氨基末端nSH2激酶连接子区域或核心脊柱残基的突变破坏调节性脊柱会导致Tec激酶失活。现在我们关注Tec家族成员Itk和Btk。关守残留物对于调节脊柱的组装也至关重要。将庞大的Itk F434网守残基突变为丙氨酸或甘氨酸可以激活Itk。 Itk F434突变体的活性可以通过随后的N端叶（特别是L432I）内的第二个位点突变来恢复。 Itk L432I突变可能通过促进调节性脊柱的组装来挽救GatekeepernF434A突变的活性。我们还显示，Itknand Btk关守残基突变为蛋氨酸足以在缺乏氨基末端SH2-激酶连接子的情况下激活Tec激酶的分离的激酶结构域。因此，通过改变守门员残基的性质来在调节脊柱的组装状态和拆卸状态之间改变构象平衡是调节Tec激酶活性的关键。

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  • 来源
    《Biochemistry》 |2011年第2期|p.221-229|共9页
  • 作者

    Raji E. Joseph and Amy H. Andreotti;

  • 作者单位

    Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, United States;

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