SEQUENCE POLYMORPHISM IN THE EPSTEIN-BARR-VIRUS LATENT MEMBRANE-PROTEIN (LMP)-2 GENE
SEQUENCE POLYMORPHISM IN THE EPSTEIN-BARR-VIRUS LATENT MEMBRANE-PROTEIN (LMP)-2 GENE
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DOI：
10.1099/0022-1317-76-1-139
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发表时间：
1995-01-01
影响因子：
3.8
通讯作者：
RAABTRAUB, N
中科院分区：
文献类型：
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作者：
BUSSON, P;EDWARDS, RH;RAABTRAUB, N
潜伏膜蛋白2A(LMP-2A)在体外表达于EB病毒转化的B淋巴细胞，并已在各种类型的EBV相关恶性肿瘤中检测到。LMP-2A通过其亲水性N-末端结构域的磷酸化和Fyn和Lyn编码的细胞酪氨酸激酶的结合来干扰膜信号转导。在体外，该结构域可以阻断钙内流，参与信号转导诱导细胞因子的产生。潜在磷酸化氨基酸残基的定点突变对这两种活性的影响是不同的。一些潜在的酪氨酸蛋白激酶识别基序已经被确定，包括一个抗原识别基序(ARAM)。ARAM被酪氨酸磷酸化激活，使其能够与Lyn和Fyn等酪氨酸蛋白激酶结合。为了评估潜在的序列变异在EBV自然感染和肿瘤发生中的重要性，我们测定了28株EBV分离株的LMP-2AN末端结构域序列，其中包括14株新鲜的肿瘤分离株。与原型B95毒株的相应序列比较表明，LMP-2通常是保守的，只有少量的碱基对变化，导致偶尔分离株的氨基酸保守变化。然而，5个单碱基基因座频繁突变，导致LMP-2A外显子1的3种序列多态。这些模式不与EBV 1型或2型分离，并在淋巴组织和上皮组织中均可检测到。166627、166750、166796和166805位点(密码子23、63、79和82)上最常见的四个突变可能会影响酪氨酸蛋白激酶结合基序。在所有分离株中，LMP-2ARAM的关键酪氨酸(密码子74和85)和亮氨酸(密码子77和88)在任何一个分离株中都没有受到影响，这表明ARAM功能在EBV体内感染中起重要作用。然而，在50%以上的分离株中，第79和82个间距位置是不同的。这些普遍存在的多态性可能会影响LMP-2胞浆结构域与特定细胞配体蛋白的相互作用。
Latent membrane protein 2A (LMP-2A) is expressed in Epstein-Barr virus transformed B lymphocytes in vitro and has been detected in various types of EBV-associated malignancies. LMP-2A interferes with membrane signal transduction through phosphorylation of its hydrophilic N-terminal domain and binding of the cellular tyrosine kinases encoded by fyn and lyn. In vitro, the domain can block calcium influx and participate in signal transduction inducing cytokine production. These two activities are differently affected by site-directed mutagenesis of potentially phosphorylated amino acid residues. Several potential tyrosine protein kinase recognition motifs have been identified including an antigen recognition motif (ARAM). ARAMs are activated by tyrosine phosphorylation that enables binding of tyrosine protein kinases such as lyn and fyn. To assess the importance of potential sequence variation in natural EBV infection and in tumourigenesis, the sequence of the LMP-2A N-terminal domain was determined in 28 EBV isolates, including 14 fresh tumour isolates. Comparison of the corresponding sequences with the prototype B95 strain indicates that LMP-2 is generally conserved with a few base pair changes resulting in conservative amino acid changes in an occasional isolate. However, five single-base loci were frequently mutated, resulting in three patterns of sequence polymorphism in exon 1 of LMP-2A. The patterns did not segregate with EBV Type 1 or Type 2 and were detected in both lymphoid and epithelial tissues. Four of the most frequent mutations at loci 166627, 166750, 166796 and 166805 (codons 23, 63, 79 and 82) could potentially affect tyrosine protein kinase binding motifs. The pivotal tyrosines (codons 74 and 85) and leucines (codons 77 and 88) of the LMP-2 ARAM were not affected in any of the isolates, suggesting that ARAM function is important for EBV infection in vivo. However, the interspacing positions 79 and 82 were distinct in more than 50% of the isolates. These prevalent polymorphisms could influence interaction of the LMP-2 cytoplasmic domain with specific cellular ligand proteins.