Substrate specificity and domain functions of extracellular heparan sulfate 6-O-endosulfatases, QSulf1 and QSulf2
Substrate specificity and domain functions of extracellular heparan sulfate 6-O-endosulfatases, QSulf1 and QSulf2
复制标题
DOI：
10.1074/jbc.m511902200
复制
发表时间：
2006-02-24
影响因子：
4.8
通讯作者：
Emerson, CP
中科院分区：
文献类型：
--
作者：
Ai, XB;Do, AT;Emerson, CP
细胞外硫酸酯酶（Sulfs）是进化上保守的硫酸乙酰肝素（HS）特异性6-O-内硫酸酯酶家族。这些酶重塑细胞表面HS链的6-O-硫酸化以促进Wnt信号传导并抑制用于胚胎组织图案化和控制肿瘤生长的生长因子信号传导。在这项研究中，我们表明，禽HS endosulfatases，QSulf 1和QSulf 2，表现出相同的底物特异性对一个子集的内部HS链的三硫酸化二糖。此外，我们表明，这两个QSulfs专门与细胞膜和细胞表面上的酶活性，以使细胞表面和细胞基质HS。突变研究表明，QSulf 1和QSulf 2的亲水结构域中的保守氨基酸区域具有多种功能，可将Sulf锚于细胞表面，与HS底物结合，并介导HS 6-O-endosulfatase酶活性。我们目前的研究结果确立了Sulf酶的亲水结构域（HD）作为其独特的内切硫酸酯酶活性的重要多功能结构域，并且还证明了Sulf在胚胎发育和肿瘤进展的细胞外信号传导控制中用于细胞表面和细胞基质HS的修饰的细胞外活性。
The extracellular sulfatases (Sulfs) are an evolutionally conserved family of heparan sulfate (HS)-specific 6-O-endosulfatases. These enzymes remodel the 6-O-sulfation of cell surface HS chains to promote Wnt signaling and inhibit growth factor signaling for embryonic tissue patterning and control of tumor growth. In this study we demonstrate that the avian HS endosulfatases, QSulf1 and QSulf2, exhibit the same substrate specificity toward a subset of trisulfated disaccharides internal to HS chains. Further, we show that both QSulfs associate exclusively with cell membrane and are enzymatically active on the cell surface to desulfate both cell surface and cell matrix HS. Mutagenesis studies reveal that conserved amino acid regions in the hydrophilic domains of QSulf1 and QSulf2 have multiple functions, to anchor Sulf to the cell surface, bind to HS substrates, and to mediate HS 6-O-endosulfatase enzymatic activity. Results of our current studies establish the hydrophilic domain (HD) of Sulf enzymes as an essential multifunctional domain for their unique endosulfatase activities and also demonstrate the extracellular activity of Sulfs for desulfation of cell surface and cell matrix HS in the control of extracellular signaling for embryonic development and tumor progression.