Involvement of Pregnancy-Associated Plasma Protein-A2 in Insulin-Like Growth Factor (IGF) Binding Protein-5 Proteolysis during Pregnancy: A Potential Mechanism for Increasing IGF Bioavailability
Involvement of Pregnancy-Associated Plasma Protein-A2 in Insulin-Like Growth Factor (IGF) Binding Protein-5 Proteolysis during Pregnancy: A Potential Mechanism for Increasing IGF Bioavailability
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DOI：
10.1210/jc.2009-2277
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发表时间：
2010-03-01
影响因子：
5.8
通讯作者：
Firth, Sue M.
中科院分区：
文献类型：
--
作者：
Yan, Xiaolang;Baxter, Robert C.;Firth, Sue M.
内容：在妊娠期间，循环中的IGF结合蛋白-5（IGFBP-5）经历了从三元复合物到二元复合物或未复合蛋白质的大量分子再分布。目的：本研究旨在表征妊娠期间循环中IGFBP-5的蛋白水解，并确定其是否可以增加IGF的生物利用度。设计：用生化方法纯化和鉴定IGFBP-5片段和IGFBP-5特异性蛋白水解活性从pregnancy plasma.Results：循环IGFBP-5在妊娠的各个阶段都被完全蛋白水解。在Ser 143或Lys 144之后切割产生两个互补片段。在妊娠血浆中鉴定的两个蛋白水解活性池（>150 kDa和类似于40 kDa）中，仅大于150 kDa的蛋白水解活性对妊娠具有特异性。大约40 kDa的蛋白水解活性，也存在于非妊娠血浆中，对IGF-I复合的IGFBP-5基本上没有活性。大于150-kDa的蛋白水解活性被α-PAPP-A2而不是α-PAPP-A1抗体抑制，在Ser 143-Lys 144处切割重组IGFBP-5，与PAPP-A2相似，并且对IGFBP-5（Ala 128）（一种PAPP-A2抗性类似物）无活性。与非妊娠血浆相比，与妊娠血浆孵育导致释放更多的生物活性IGF-I从IGF-I-IGFBP-5复合物的IGF-I刺激IGF-I受体phosphorylation.Conclusions：循环IGFBP-5是蛋白水解PAPP-A2在怀孕期间，导致IGF生物利用度增加，这可能有重要的后果胎儿的发展和/或母亲的福祉。（临床内分泌代谢杂志95：1412-1420，2010）
Context: During pregnancy, circulating IGF binding protein-5 (IGFBP-5) undergoes substantial molecular redistribution from ternary complexes to either binary complexes or the uncomplexed protein.Objective: This study aimed to characterize the proteolysis of circulating IGFBP-5 during pregnancy and to determine whether it can increase IGF bioavailability.Design: Biochemical methods were used to purify and characterize IGFBP-5 fragments and IGFBP-5-specific proteolytic activity from pregnancy plasma.Results: Circulating IGFBP-5 was fully proteolyzed at all stages of pregnancy. Cleavage after either Ser143 or Lys144 resulted in two complementary fragments. Of two pools of proteolytic activity (>150 kDa and similar to 40 kDa) identified in pregnancy plasma, only the greater than 150-kDa proteolytic activity was specific to pregnancy. The approximately 40-kDa proteolytic activity, also present in nonpregnancy plasma, appeared largely inactive against IGF-I-complexed IGFBP-5. The greater than 150-kDa proteolytic activity was inhibited by alpha-PAPP-A2 but not alpha-PAPP-A1 antibody, cleaved recombinant IGFBP-5 at Ser143-Lys144 similar to PAPP-A2, and was inactive against IGFBP-5 (Ala128), a PAPP-A2-resistant analog. Compared to nonpregnancy plasma, incubation with pregnancy plasma resulted in release of more bioactive IGF-I from IGF-I-IGFBP-5 complexes as measured by stimulation of IGF-I receptor phosphorylation.Conclusions: Circulating IGFBP-5 is proteolyzed by PAPP-A2 during pregnancy, resulting in increased IGF bioavailability, which may have important consequences for the development of the fetus and/or the well-being of the mother. (J Clin Endocrinol Metab 95: 1412-1420, 2010)