Impaired secretion of rat mannose-binding protein resulting from mutations in the collagen-like domain
Impaired secretion of rat mannose-binding protein resulting from mutations in the collagen-like domain
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DOI：
10.4049/jimmunol.165.3.1403
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发表时间：
2000-08-01
影响因子：
4.4
通讯作者：
Wallis, R
中科院分区：
文献类型：
--
作者：
Heise, CT;Nicholls, JR;Wallis, R
血清甘露糖结合蛋白（MBP）或甘露糖结合凝集素通过与潜在病原微生物表面结合并通过n端胶原样结构域启动补体固定，启动先天免疫反应的凝集素分支。人类MBP这一区域的突变与免疫缺陷有关，这是由于突变的MBPs固定补体的能力降低以及血清浓度降低造成的。突变蛋白的低效分泌是血清水平降低的一个可能原因，研究人员使用哺乳动物表达系统进行了研究，在该系统中，每种自然发生的人类突变都在大鼠血清MBP中重现。突变Gly(25)- >Asp和Gly28- >Glu破坏了蛋白质的二硫键排列，导致MBP分泌的半衰期比野生型大鼠血清MBP至少增加了5倍。当27位和30位附近的葡萄糖半乳糖羟赖氨酸残基被精氨酸残基取代时，观察到类似的表型，包括分泌半衰期增加3倍，二硫键排列破坏，补体固定效率低下。结果表明，由胶原样结构域的结构变化引起的分泌缺陷可能是导致MBP免疫缺陷的一个因素。
Serum mannose-binding protein (MBP) or mannose-binding lectin initiates the lectin branch of the innate immune response by binding to the surface of potentially pathogenic microorganisms and initiating complement fixation through an N-terminal collagen-like domain. Mutations in this region of human MBP are associated with immunodeficiency resulting from a reduction in the ability of the mutant MBPs to fix complement as well as from reduced serum concentrations. Inefficient secretion of the mutant proteins, which is one possible cause of the reduced serum levels, has been investigated using a mammalian expression system in which each of the naturally occurring human mutations has been recreated in rat serum MBP. The mutations Gly(25)-->Asp and Gly28-->Glu disrupt the disulfide-bonding arrangement of the protein and cause at least a 5-fold increase in the half-time of secretion of MBP compared with wild-type rat serum MBP. A similar phenotype, including a 3-fold increase in the half-time of secretion, disruption of the disulfide bonding arrangement, and inefficient complement fixation, is observed when nearby glucosylgalactosyl hydroxylysine residues at positions 27 and 30 are replaced with arginine residues, The results suggest that defective secretion resulting from structural changes in the collagen-like domain is likely to be a contributory factor for MBP immunodeficiency.