Vaspin inhibits kallikrein 7 by serpin mechanism.
Vaspin inhibits kallikrein 7 by serpin mechanism.
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DOI：
10.1007/s00018-013-1258-8
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发表时间：
2013-07
影响因子：
8
通讯作者：
Beck-Sickinger, Annette G.
中科院分区：
文献类型：
--
作者：
Heiker, John T.;Kloeting, Nora;Kovacs, Peter;Kuettner, E. Bartholomeus;Straeter, Norbert;Schultz, Stephan;Kern, Matthias;Stumvoll, Michael;Blueher, Matthias;Beck-Sickinger, Annette G.
脂肪因子vaspin（内脏脂肪组织来源的蛇形蛋白；serpinA12）的分子靶点及其作用方式尚不清楚。在此，我们提供了vaspin的晶体结构，并在体外高特异性地鉴定了人类kallikrein 7 （hK7）作为vaspin受经典丝素机制抑制的第一个蛋白酶靶点。我们在人血浆中检测了vaspin-hK7复合物，并在小鼠胰腺β-细胞中发现了这两种蛋白的共表达。我们进一步证明hK7在A链和b链上切割人胰岛素。用Vaspin治疗离体胰岛可导致葡萄糖刺激后介质中胰岛素浓度升高，但不影响胰岛素分泌。通过应用vaspin和生成的失活突变体，我们发现重组vaspin处理C57BL/6NTac和db/db小鼠的葡萄糖耐量显著改善，完全依赖于vaspin丝氨酸蛋白活性，与vaspin介导的胰岛素敏感性变化无关，这是由正糖-高胰岛素钳夹研究确定的。在db/db小鼠中，葡萄糖刺激后150分钟胰岛素血浆浓度升高可介导葡萄糖代谢的改善，这支持了血管素可能抑制循环中hK7对胰岛素降解的假设。总之，我们证明了抑制蛇形蛋白的性质和脂肪组织来源的蛇形蛋白vaspin的第一个蛋白酶靶点，我们的研究结果表明，vaspin对hK7的抑制是其对肥胖诱导的胰岛素抵抗的补偿作用的潜在生理机制。本文的在线版本（doi:10.1007/s00018-013-1258-8）包含补充资料，仅供授权用户使用。
The molecular target of the adipokine vaspin (visceral adipose tissue-derived serpin; serpinA12) and its mode of action are unknown. Here, we provide the vaspin crystal structure and identify human kallikrein 7 (hK7) as a first protease target of vaspin inhibited by classical serpin mechanism with high specificity in vitro. We detect vaspin–hK7 complexes in human plasma and find co-expression of both proteins in murine pancreatic β-cells. We further demonstrate that hK7 cleaves human insulin in the A- and B-chain. Vaspin treatment of isolated pancreatic islets leads to increased insulin concentration in the media upon glucose stimulation without influencing insulin secretion. By application of vaspin and generated inactive mutants, we find the significantly improved glucose tolerance in C57BL/6NTac and db/db mice treated with recombinant vaspin fully dependent on the vaspin serpin activity and not related to vaspin-mediated changes in insulin sensitivity as determined by euglycemic-hyperinsulinemic clamp studies. Improved glucose metabolism could be mediated by increased insulin plasma concentrations 150 min after a glucose challenge in db/db mice, supporting the hypothesis that vaspin may inhibit insulin degradation by hK7 in the circulation. In conclusion, we demonstrate the inhibitory serpin nature and the first protease target of the adipose tissue-derived serpin vaspin, and our findings suggest hK7 inhibition by vaspin as an underlying physiological mechanism for its compensatory actions on obesity-induced insulin resistance. The online version of this article (doi:10.1007/s00018-013-1258-8) contains supplementary material, which is available to authorized users.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444904016427
发表时间：
2004-12-01
影响因子：
2.2
作者：
Blanc, E;Roversi, P;Bricogne, G
通讯作者：
Bricogne, G
影响因子：
11.2
作者：
Dong, Ying;Tan, Olivia L.;Clements, Judith A.
通讯作者：
Clements, Judith A.
影响因子：
6.2
作者：
Johnson, Sarah K.;Rarnani, Vishnu C.;Haun, Randy S.
通讯作者：
Haun, Randy S.
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC