妊娠相关血浆蛋白-A（PAPPA）基因的常见变体编码的蛋白对IGF结合蛋白的蛋白水解活性降低。,Scientific Reports

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妊娠相关血浆蛋白-A（PAPPA）基因的常见变体编码的蛋白对IGF结合蛋白的蛋白水解活性降低。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-09-13 , DOI: 10.1038/s41598-019-49626-8
Jane Alrø Bøtkjær ₁ , Pernille Rimmer Noer ₂ , Claus Oxvig ₂ , Claus Yding Andersen ₁

Affiliation

怀孕相关血浆蛋白A（PAPP-A）是胰岛素样生长因子（IGF）生物活性的关键调节剂，它通过从其相应的IGF结合蛋白（IGFBPs）中释放IGF来发挥作用。PAPPA中单核苷酸多态性（SNP）的rs7020782（丝氨酸<酪氨酸）的次要等位基因以前与复发性流产以及人类卵巢卵泡中PAPP-A蛋白的显着降低有关。本研究的目的是通过比较转染的人胚肾293 T细胞的重组PAPP-A蛋白来揭示rs7020782 SNP在PAPPA中的可能功能作用。IGFBP-4的蛋白水解切割显示受PAPPA中的rs7020782 SNP影响，与酪氨酸变体相比，丝氨酸变体的切割率显着降低（p值<0.001）。与酪氨酸变体相比，丝氨酸变体还显示出对IGFBP-2和IGFBP-5的切割速率降低的趋势，这并不显着。分析细胞表面结合，PAPP-A与STC2或proMBP之间的复合物形成，或分析STC1对PAPP-A介导的IGFBP-4裂解的抑制作用时，均未发现差异。生殖组织中IGF生物活性的调节很重要，PAPPA中的rs7020782 SNP可能会通过改变PAPP-A的比活性来干扰这种调节。在分析STC1对PAPP-A介导的IGFBP-4裂解的抑制作用时也是如此。生殖组织中IGF生物活性的调节很重要，PAPPA中的rs7020782 SNP可能会通过改变PAPP-A的比活性来干扰这种调节。在分析STC1对PAPP-A介导的IGFBP-4裂解的抑制作用时也是如此。生殖组织中IGF生物活性的调节很重要，PAPPA中的rs7020782 SNP可能会通过改变PAPP-A的比活性来干扰这种调节。

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A common variant of the pregnancy-associated plasma protein-A (PAPPA) gene encodes a protein with reduced proteolytic activity towards IGF-binding proteins.

Pregnancy-associated plasma protein-A (PAPP-A) is a key regulator of insulin-like growth factor (IGF) bioactivity, by releasing the IGFs from their corresponding IGF-binding proteins (IGFBPs). The minor allele of the single nucleotide polymorphism (SNP), rs7020782 (serine < tyrosine), in PAPPA has previously been associated with recurrent pregnancy loss as well as with significant reduced levels of PAPP-A protein in human ovarian follicles. The aim of the present study was to reveal a possible functional effect of the rs7020782 SNP in PAPPA by comparing recombinant PAPP-A proteins from transfected human embryonic kidney 293 T cells. The proteolytic cleavage of IGFBP-4 was shown to be affected by the rs7020782 SNP in PAPPA, showing a significantly reduced cleavage rate for the serine variant compared to the tyrosine variant (p-value < 0.001). The serine variant also showed a trend towards reduced cleavage rates, that was not significant, towards IGFBP-2 and IGFBP-5 compared to the tyrosine variant. No differences were found when analysing cell surface binding, complex formation between PAPP-A and STC2 or proMBP, nor when analysing STC1 inhibition of PAPP-A-mediated IGFBP-4 cleavage. Regulation of IGF bioactivity in reproductive tissues is important and the rs7020782 SNP in PAPPA may disturb this regulation by altering the specific activity of PAPP-A.

更新日期：2019-09-14

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