Busson P, Edwards R H, Tursz T, Raab-Traub N
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill 27599-7295.
J Gen Virol. 1995 Jan;76 ( Pt 1):139-45. doi: 10.1099/0022-1317-76-1-139.
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 inter-spacing 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.
潜伏膜蛋白2A（LMP-2A）在体外的爱泼斯坦-巴尔病毒转化的B淋巴细胞中表达，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端结构域的磷酸化以及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，该结构域可以阻止钙内流并参与诱导细胞因子产生的信号转导。这两种活性受到潜在磷酸化氨基酸残基定点诱变的不同影响。已经鉴定出几种潜在的酪氨酸蛋白激酶识别基序，包括抗原识别基序（ARAM）。ARAM通过酪氨酸磷酸化被激活，从而能够结合酪氨酸蛋白激酶，如lyn和fyn。为了评估自然EBV感染和肿瘤发生中潜在序列变异的重要性，在28株EBV分离株中测定了LMP-2A N端结构域的序列，其中包括14株新鲜肿瘤分离株。将相应序列与原型B95株进行比较表明，LMP-2通常是保守的，只有少数碱基对变化，偶尔会导致个别分离株中氨基酸发生保守变化。然而，五个单碱基位点经常发生突变，导致LMP-2A外显子1出现三种序列多态性模式。这些模式与EBV 1型或2型没有分离，并且在淋巴组织和上皮组织中均有检测到。位点166627、166750、166796和166805（密码子23、63、79和82）处最常见的四个突变可能会影响酪氨酸蛋白激酶结合基序。LMP-2 ARAM的关键酪氨酸（密码子74和85）和亮氨酸（密码子77和88）在任何分离株中均未受影响，这表明ARAM功能对于体内EBV感染很重要。然而，超过50%的分离株中79和82的间隔位置不同。这些普遍存在的多态性可能会影响LMP-2胞质结构域与特定细胞配体蛋白的相互作用。
