Catabolism of asialo-GM2 in man and mouse - Specificity of human/mouse chimeric GM2 activator proteins
Catabolism of asialo-GM2 in man and mouse - Specificity of human/mouse chimeric GM2 activator proteins
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DOI：
10.1074/jbc.274.40.28612
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发表时间：
1999-10-01
影响因子：
4.8
通讯作者：
Li, SC
中科院分区：
文献类型：
--
作者：
Bertoni, C;Li, YT;Li, SC
泰-萨克斯病是一种先天性溶酶体疾病，其特征是GM2在大脑中过度积聚。在人体内，GM2分解代谢为GM3需要β -己糖胺酶A（HexA）和一种蛋白质辅因子，即GM2激活剂。因此，泰-萨克斯病可由HexA或GM2激活剂的缺乏引起。在小鼠中发现的相同辅因子与人类的相应辅因子有74.1%的氨基酸同一性（67%的核苷酸同一性）。在这两种激活剂之间，小鼠GM2激活剂能有效地刺激HexA对GM2和无唾液酸GM2（GA2）的水解，并且在较小程度上也能刺激HexB水解GA2，而人类激活剂在刺激GA2水解方面是无效的（Yuziuk，J.A.，Bertoni，C.，Beccari，T.，Orlacchio，A.，Wu，Y.-Y.，Li，S.-C.，和Li，Y.-T.（1998）J. Biol. Chem. 273，66 - 72）。为了了解这两种激活剂在刺激GM2和GA2水解中的作用，我们构建了人/鼠嵌合GM2激活剂并研究了它们的特异性。我们在小鼠cDNA序列中确定了一个狭窄区域（Asn(106)-Tyr(114)），它可能负责刺激GA2的水解。用特定的小鼠序列替换人类序列中的相应位点，将无效的人类激活剂转化为一种能有效刺激GA2水解的嵌合蛋白。这种嵌合激活剂蛋白，像小鼠蛋白一样，也能够刺激HexB对GA2的水解。最近通过对Hexa基因进行靶向破坏而构建的人类B型泰-萨克斯病小鼠模型，其临床表现比人类患者的症状轻。这被认为是由于在小鼠GM2激活剂蛋白的协助下，GM2通过转化为GA2以及HexB进一步将GA2水解为乳糖基神经酰胺而进行分解代谢的结果。因此，具有小鼠GM2激活剂特征的嵌合激活剂蛋白可能能够在人类B型泰-萨克斯病患者中诱导一种GM2的替代分解代谢途径。
Tay-Sachs disease is an inborn lysosomal disease characterized by excessive cerebral accumulation of GM2. The catabolism of GM2 to GM3 in man requires beta-hexosaminidase A (HexA) and a protein cofactor, the GM2 activator. Thus, Tay-Sachs disease can be caused by the deficiency of either HexA or the GM2 activator. The same cofactor found in mouse shares 74.1% amino acid identity (67% nucleotide identity) with the human counterpart. Between the two activators, the mouse GM2 activator can effectively stimulate the hydrolysis of both GM2 and asialo-GM2 (GA2) by HexA and, to a lesser extent, also stimulate HexB to hydrolyze GA2, whereas the human activator is ineffective in stimulating the hydrolysis of GA2 (Yuziuk, J. A., Bertoni, C., Beccari, T., Orlacchio, A., Wu, Y.-Y., Li, S.-C., and Li, Y.-T. (1998) J, Biol, Chem. 273, 66-72), To understand the role of these two activators in stimulating the hydrolyses of GM2 and GA2, we have constructed human/mouse chimeric GM2 activators and studied their specificities. We have identified a narrow region (Asn(106)-Tyr(114)) in the mouse cDNA sequence that might be responsible for stimulating the hydrolysis of GA2, Replacement of the corresponding site in the human sequence with the specific mouse sequence converted the ineffective human activator into an effective chimeric protein for stimulating the hydrolysis of GA2, This chimeric activator protein, like the mouse protein, is also able to stimulate the hydrolysis of GA2 by HexB, The mouse model of human type B Tay-Sachs disease recently engineered by the targeted disruption of the Hexa gene showed less severe clinical manifestation than found in human patients. This has been considered to be the result of the catabolism of GM2 via converting it to GA2 and further hydrolysis of GA2 to lactosylceramide by HexB with the assistance of mouse GM2 activator protein. The chimeric activator protein that bears the characteristics of the mouse GM2 activator may therefore be able to induce an alternative catabolic pathway for GM2 in human type B Tay-Sachs patients.