Conserved residues amino-terminal of cytoplasmic tyrosines contribute to the SHP-1-mediated inhibitory function of killer cell Ig-like receptors.
Conserved residues amino-terminal of cytoplasmic tyrosines contribute to the SHP-1-mediated inhibitory function of killer cell Ig-like receptors.
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DOI：
10.4049/jimmunol.162.2.897
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发表时间：
1999-01
影响因子：
4.4
通讯作者：
D. Burshtyn;A. S. Lam;M. Weston;N. Gupta;P. Warmerdam;Eric O Long
中科院分区：
文献类型：
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作者：
D. Burshtyn;A. S. Lam;M. Weston;N. Gupta;P. Warmerdam;Eric O Long
序列I/VxYxxL通常被称为基于免疫受体酪氨酸的抑制基序(ITIM)，与酪氨酸磷酸酶SHP-1的C-末端Src同源2结构域结合。酪氨酸的保守残基N端在其他的Src同源2结构域结合基序中是不常见的。杀伤细胞免疫球蛋白样受体(KIR)的抑制形式包含两个ITIMs。通过痘苗病毒介导的突变kir的表达来检测每个ITIM以及酪氨酸上游的保守残基在抑制NK细胞中的作用。膜-近端ITIM酪氨酸的替代使KIR阻断抗体依赖的细胞毒作用的能力减弱，而膜-远端ITIM酪氨酸突变对此影响不大。将位于两个N-端的保守疏水氨基酸替换到酪氨酸上，减弱了受体的功能，但没有消除。相反，这些取代大大减少了SHP-1与KIR的免疫沉淀量，表明与SHP-1的弱相互作用可能足以抑制。
The sequence I/VxYxxL, often referred to as an immunoreceptor tyrosine-based inhibition motif (ITIM), binds to the C-terminal Src homology 2 domain of the tyrosine phosphatase SHP-1. Conserved residues N-terminal of the tyrosine are not ordinarily found in other Src homology 2 domain binding motifs. The inhibitory forms of killer cell Ig-like receptors (KIR) contain two ITIMs. The role of each ITIM, and of the conserved residues upstream of the tyrosine, in the inhibition of NK cells was tested by vaccinia virus-mediated expression of mutant KIRs. Substitution of the tyrosine in the membrane-proximal ITIM abrogated the ability of KIR to block Ab-dependent cellular cytotoxicity, whereas mutation of the membrane-distal ITIM tyrosine had little effect. Substitution of the conserved hydrophobic amino acid that was located two residues N-terminal to the tyrosine weakened, but did not eliminate, the function of the receptor. In contrast, these substitutions drastically reduced the amount of SHP-1 immunoprecipitated with KIR, suggesting that weak interactions with SHP-1 may be sufficient for inhibition.