ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein
ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein
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DOI：
10.1096/fj.05-3877fje
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发表时间：
2006-05-01
期刊：
影响因子：
4.8
通讯作者：
Di Cesare, Paul E.
中科院分区：
文献类型：
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作者：
Liu, Chuan-ju;Kong, Wei;Di Cesare, Paul E.
在关节炎患者中观察到软骨寡聚基质蛋白（COMP）的降解片段。然而，降解COMP的生理酶仍然未知。我们进行了酵母双杂交筛选（Y2 H），以寻找与COMP相关的蛋白质，以确定可能降解COMP的相互作用伴侣。一个筛选使用COMP的表皮生长因子（EGF）结构域作为诱饵，导致ADAMTS-7的发现。大鼠ADAMTS-7由1595个氨基酸组成，并且该蛋白在肌肉骨骼组织中表现出较高的表达。COMP在体外和天然关节软骨中直接结合ADAMTS-7。ADAMTS-7选择性地与EGF重复结构域相互作用，但不与COMP的其他三个功能结构域相互作用，而ADAMTS-7的四个C-末端TSP基序是必需的，足以与COMP相关联。重组催化结构域和完整的ADAMTS-7能够在体外消化COMP。ADAMTS-7的酶活性需要Zn 2+的存在和适当的pH（7.5-9.5），并且与正常软骨和滑膜相比，类风湿性关节炎患者的软骨和滑膜中ADAMTS-7的浓度显著增加。ADAMTS-7是发现的第一个直接结合并降解COMP的金属蛋白酶。
Degradative fragments of cartilage oligomeric matrix protein (COMP) have been observed in arthritic patients. The physiological enzyme(s) that degrade COMP, however, remain unknown. We performed a yeast two-hybrid screen (Y2H) to search for proteins that associate with COMP to identify an interaction partner that might degrade it. One screen using the epidermal growth factor (EGF) domain of COMP as bait led to the discovery of ADAMTS-7. Rat ADAMTS-7 is composed of 1595 amino acids, and this protein exhibits higher expression in the musculoskeletal tissues. COMP binds directly to ADAMTS-7 in vitro and in native articular cartilage. ADAMTS-7 selectively interacts with the EGF repeat domain but not with the other three functional domains of COMP, whereas the four C-terminal TSP motifs of ADAMTS-7 are required and sufficient for association with COMP. The recombinant catalytic domain and intact ADAMTS-7 are capable of digesting COMP in vitro. The enzymatic activity of ADAMTS-7 requires the presence of Zn2+ and appropriate pH (7.5-9.5), and the concentration of ADAMTS-7 in cartilage and synovium of patients with rheumatoid arthritis is significantly increased as compared to normal cartilage and synovium. ADAMTS-7 is the first metalloproteinase found to bind directly to and degrade COMP.