Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A
Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A
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DOI：
10.1016/s0014-5793(01)02760-0
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发表时间：
2001-08-24
期刊：
影响因子：
3.5
通讯作者：
Oxvig, C
中科院分区：
文献类型：
--
作者：
Laursen, LS;Overgaard, MT;Oxvig, C
妊娠相关血浆蛋白-a （PAPP-A）最近被确定为几种生物体液中负责胰岛素样生长因子结合蛋白(IGFBP)-4裂解的蛋白酶，IGFBP -4是IGF作用的抑制剂。PAPP-A对IGFBP-4的切割被认为只发生在IGF存在的情况下。我们在这里报道，除了IGFBP-4， PAPP-A也切割IGFBP-5。切割发生在IGFBP-5的Ser-143和Lys-144位点之间。在IGF存在的情况下，IGFBP-4和-5被PAPP-A以相似的速率切割。有趣的是，PAPP-A对IGFBP-5的切割不需要IGF的存在，而是被IGF轻微抑制。这些发现暗示了IGFBP-4被PAPP-A蛋白水解的机制，表明IGFBP-4结合IGF，然后成为PAPP-A底物。利用高纯度的重组蛋白，我们证实了(1)IGFBP-4在没有IGF的情况下可以发生PAPP-A的裂解，尽管水解速度非常慢；(2)IGF不能与PAPP-A结合。因此，我们得出结论，IGF通过与IGFBP-4结合而不是通过与PAPP-A相互作用来增强蛋白水解，这在之前是不能排除的。(C) 2001年欧洲生化学会联合会。Elsevier Science B.V.版权所有。
Pregnancy-associated plasma protein-A (PAPP-A) has recently been identified as the proteinase responsible for cleavage of insulin-like growth factor binding protein (IGFBP)-4, an inhibitor of IGF action, in several biological fluids. Cleavage of IGFBP-4 by PAPP-A is believed to occur only in the presence of IGF. We here report that in addition to IGFBP-4, PAPP-A also cleaves IGFBP-5. Cleavage occurs at one site, between Ser-143 and Lys-144 of IGFBP-5. In the presence of IGF, IGFBP-4 and -5 are cleaved with similar rates by PAPP-A. Interestingly, cleavage of IGFBP-5 by PAPP-A does not require the presence of IGF, but is slightly inhibited by IGF. These findings have implications for the mechanism of proteolysis of IGFBP-4 by PAPP-A, suggesting that IGFBP-4 binds IGF, which then becomes a PAPP-A substrate. Using highly purified, recombinant proteins, we establish that (1) PAPP-A cleavage of IGFBP-4 can occur in the absence of IGF, although the rate of hydrolysis is very slow, and (2) IGF is unable to bind to PAPP-A. We thus conclude that IGF enhances proteolysis by binding to IGFBP-4, not by interaction with PAPP-A, which could not previously be ruled out. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.