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首页> 外文期刊>Biochemistry >Mechanism by which heparin proteoglycan modulates mast cell chymase activity.
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Mechanism by which heparin proteoglycan modulates mast cell chymase activity.

机译：肝素蛋白聚糖调节肥大细胞糜酶活性的机制。

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摘要

Chymases are highly basic chymotrypsin-like serine proteases expressed exclusively by mast cells. Large amounts of chymases complexed with heparin proteoglycan (PG) are released in vivo during mast cell activation. The tight binding of chymase to heparin PG results in increased activity of the protease toward certain substrates, e.g., thrombin and MeO-Suc-Arg-Pro-Tyr-pNA (S-2586). In this study, the mechanism by which heparin PG modulates chymase activity was investigated, using thrombin and various chromogenic peptide substrates as model substrates. Incubation of thrombin with oligonucleotides that block the heparin-binding site of thrombin abolished the stimulatory effect of heparin PG on thrombin inactivation. Further, thrombin mutants with defects in their heparin-binding regions were less efficiently inactivated by chymase-heparin PG than wild type thrombin. These findings suggest a model for chymase stimulation where heparin PG may promote the chymase-catalyzed cleavage of heparin-binding substrates by simultaneously binding to both chymase and substrate. Experiments in which various chromogenic peptide substrates were utilized showed that heparin PG enhanced the activity of chymase toward positively charged peptide substrates such as S-2586, whereas the cleavage of uncharged substrates was not affected by the presence of heparin PG. On the basis of the latter findings, an alternative stimulation mechanism is discussed where heparin PG may stimulate chymase activity by blocking positively charged regions in chymase, thereby reducing the level of electrostatic repulsion between chymase and positively charged substrates.
机译：胸腺癌是仅由肥大细胞表达的高度碱性的胰凝乳蛋白酶样丝氨酸蛋白酶。肥大细胞激活过程中，体内释放出大量与肝素蛋白聚糖（PG）复合的乳糜。糜蛋白酶与肝素PG的紧密结合导致蛋白酶对某些底物（例如凝血酶和MeO-Suc-Arg-Pro-Tyr-pNA（S-2586））的活性增加。在这项研究中，使用凝血酶和各种生色肽底物作为模型底物，研究了肝素PG调节糜酶活性的机制。将凝血酶与可阻断凝血酶肝素结合位点的寡核苷酸一起孵育，消除了肝素PG对凝血酶失活的刺激作用。此外，与野生型凝血酶相比，由糜酶-肝素PG灭活肝素结合区缺陷的凝血酶突变体效率较低。这些发现提示了一种糜酶刺激模型，其中肝素PG可通过同时与糜酶和底物结合来促进肝素结合底物的糜酶催化裂解。利用各种生色肽底物的实验表明，肝素PG增强了糜酶对带正电荷的肽底物（如S-2586）的活性，而肝素PG的存在不影响不带电底物的裂解。基于后者的发现，讨论了另一种刺激机制，其中肝素PG可通过阻断糜酶中带正电荷的区域来刺激糜酶活性，从而降低糜酶与带正电荷的底物之间的静电排斥水平。

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