Fedarko Neal S, Jain Alka, Karadag Abdullah, Fisher Larry W
Division of Geriatrics, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
FASEB J. 2004 Apr;18(6):734-6. doi: 10.1096/fj.03-0966fje. Epub 2004 Feb 6.
Matrix metalloproteinases (MMPs) are critical for development, wound healing, and for the progression of cancer. It is generally accepted that MMPs are secreted in a latent form (proMMP) and are activated only upon removal of their inhibitory propeptides. This report shows that three members of the SIBLING (Small, Integrin-Binding LIgand, N-linked Glycoprotein) family can specifically bind (Kd approximately equal nM) and activate three different MMPs. Binding of SIBLING to their corresponding proMMPs is associated with structural changes as indicated by quenching of intrinsic tryptophan fluorescence, increased susceptibility to plasmin cleavage, and decreased inhibition by specific natural and synthetic inhibitors. Activation includes both making the proMMPs enzymatically active and the reactivation of the TIMP (tissue inhibitors of MMP) inhibited MMPs. Bone sialoprotein specifically binds proMMP-2 and active MMP-2, while osteopontin binds proMMP-3 and active MMP-3, and dentin matrix protein-1 binds proMMP-9 and active MMP-9. Both pro and active MMP-SIBLING complexes are disrupted by the abundant serum protein, complement Factor H, thereby probably limiting SIBLING-mediated activation to regions immediately adjacent to sites of secretion in vivo. These data suggest that the SIBLING family offers an alternative method of controlling the activity of at least three MMPs.
基质金属蛋白酶（MMPs）对发育、伤口愈合及癌症进展至关重要。人们普遍认为，MMPs以无活性形式（前MMP）分泌，仅在去除其抑制性前肽后才被激活。本报告显示，SIBLING（小整合素结合配体N-连接糖蛋白）家族的三个成员可特异性结合（解离常数约为纳摩尔）并激活三种不同的MMPs。SIBLING与其相应的前MMPs结合会伴随结构变化，表现为内在色氨酸荧光淬灭、对纤溶酶切割的敏感性增加以及对特定天然和合成抑制剂的抑制作用降低。激活过程包括使前MMPs具有酶活性以及使被基质金属蛋白酶组织抑制剂（TIMP）抑制的MMPs重新激活。骨唾液蛋白特异性结合前MMP-2和活性MMP-2，骨桥蛋白结合前MMP-3和活性MMP-3，牙本质基质蛋白-1结合前MMP-9和活性MMP-9。前MMP-SIBLING复合物和活性MMP-SIBLING复合物均会被丰富的血清蛋白补体因子H破坏，因此可能将SIBLING介导的激活限制在体内紧邻分泌部位的区域。这些数据表明，SIBLING家族提供了一种控制至少三种MMPs活性的替代方法。
