Van den Steen Philippe E, Van Aelst Ilse, Hvidberg Vibeke, Piccard Helene, Fiten Pierre, Jacobsen Christian, Moestrup Soren K, Fry Simon, Royle Louise, Wormald Mark R, Wallis Russell, Rudd Pauline M, Dwek Raymond A, Opdenakker Ghislain
Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, B-3000, Belgium.
J Biol Chem. 2006 Jul 7;281(27):18626-37. doi: 10.1074/jbc.M512308200. Epub 2006 May 3.
Gelatinase B/matrix metalloproteinase-9 (MMP-9), a key regulator and effector of immunity, contains a C-terminal hemopexin domain preceded by a unique linker sequence of approximately 64 amino acid residues. This linker sequence is demonstrated to be an extensively O-glycosylated (OG) domain with a compact three-dimensional structure. The OG and hemopexin domains have no influence on the cleavage efficiency of MMP-9 substrates. In contrast, the hemopexin domain contains a binding site for the cargo receptor low density lipoprotein receptor-related protein-1 (LRP-1). Furthermore, megalin/LRP-2 is identified as a new functional receptor for the hemopexin domain of MMP-9, able to mediate the endocytosis and catabolism of the enzyme. The OG domain is required to correctly orient the hemopexin domain for inhibition by TIMP-1 and internalization by LRP-1 and megalin. Therefore, the OG and hemopexin domains down-regulate the bioavailability of active MMP-9 and the interactions with the cargo receptors are proposed to be the original function of hemopexin domains in MMPs.
明胶酶B/基质金属蛋白酶-9（MMP-9）是免疫的关键调节因子和效应分子，其C端血色素结合蛋白结构域之前有一段约64个氨基酸残基的独特连接序列。该连接序列被证明是一个具有紧密三维结构的广泛O-糖基化（OG）结构域。OG结构域和血色素结合蛋白结构域对MMP-9底物的切割效率没有影响。相反，血色素结合蛋白结构域含有货物受体低密度脂蛋白受体相关蛋白-1（LRP-1）的结合位点。此外，巨膜蛋白/LRP-2被鉴定为MMP-9血色素结合蛋白结构域的一种新的功能性受体，能够介导该酶的内吞作用和分解代谢。OG结构域是使血色素结合蛋白结构域正确定向以被TIMP-1抑制以及被LRP-1和巨膜蛋白内化所必需的。因此，OG结构域和血色素结合蛋白结构域下调活性MMP-9的生物利用度，并且与货物受体的相互作用被认为是MMPs中血色素结合蛋白结构域的原始功能。
