Basic residues of human group IIA phospholipase A2 are important for binding to factor Xa and prothrombinase inhibition comparison with other mammalian secreted phospholipases A2.
Basic residues of human group IIA phospholipase A2 are important for binding to factor Xa and prothrombinase inhibition comparison with other mammalian secreted phospholipases A2.
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与其他哺乳动物分泌的磷脂酶 A2 相比，人 IIA 族磷脂酶 A2 的碱性残基对于结合 Xa 因子和凝血酶原酶抑制非常重要。
DOI：
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
C. Bon
中科院分区：
文献类型：
--
作者：
C. Mounier;P. Luchetta;C. Lecut;R. Koduri;G. Faure;G. Lambeau;E. Valentin;A. Singer;F. Ghomashchi;S. Béguin;M. Gelb;C. Bon
人分泌型IIA磷脂酶A2(HGIIA)通过与凝血因子Xa结合而抑制凝血酶原酶的活性。本研究进一步表明，hGIIA及其催化失活的H48Q突变体以相似的效率延长了人富血小板血浆中凝血酶生成的滞后时间，表明hGIIA在体外条件下具有不依赖于磷脂水解的抗凝作用。HGIIA界面结合表面(IBS)上碱性残基的电荷反转导致抑制凝血酶原酶活性的能力降低，这与表面等离子体共振确定的Xa因子亲和力降低有关。其他表面暴露的碱性残基、IBS上的疏水残基和His48的突变不影响hGIIA抑制凝血酶原酶活性和与Xa因子结合的能力。其他非中性或酸性的碱性磷脂酶A2(SPLA2)对凝血酶原酶的活性具有非磷脂依赖性的抑制作用，提示这些碱性sPLA2也与凝血因子Xa结合。综上所述，本研究表明，即使在体外条件下，hGIIA的抗凝作用也不依赖于磷脂的水解，而是基于其与凝血因子Xa的相互作用，从而导致凝血酶原酶的抑制。这项研究还表明，这种相互作用涉及位于hGIIA IBS上的碱性残基，并表明其他碱性哺乳动物sPLA2也可能通过与hGIIA类似的机制抑制凝血。
Human secreted group IIA phospholipase A2 (hGIIA) was reported to inhibit prothrombinase activity because of binding to factor Xa. This study further shows that hGIIA and its catalytically inactive H48Q mutant prolong the lag time of thrombin generation in human platelet-rich plasma with similar efficiency, indicating that hGIIA exerts an anticoagulant effect independently of phospholipid hydrolysis under ex vivo conditions. Charge reversal of basic residues on the interfacial binding surface (IBS) of hGIIA leads to decreased ability to inhibit prothrombinase activity, which correlates with a reduced affinity for factor Xa, as determined by surface plasmon resonance. Mutation of other surface-exposed basic residues, hydrophobic residues on the IBS, and His48, does not affect the ability of hGIIA to inhibit prothrombinase activity and bind to factor Xa. Other basic, but not neutral or acidic, mammalian secreted phospholipases A2 (sPLA2s) exert a phospholipid-independent inhibitory effect on prothrombinase activity, suggesting that these basic sPLA2s also bind to factor Xa. In conclusion, this study demonstrates that the anticoagulant effect of hGIIA is independent of phospholipid hydrolysis and is based on its interaction with factor Xa, leading to prothrombinase inhibition, even under ex vivo conditions. This study also shows that such an interaction involves basic residues located on the IBS of hGIIA, and suggests that other basic mammalian sPLA2s may also inhibit blood coagulation by a similar mechanism to that described for hGIIA.
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DOI：
10.1074/jbc.274.44.31195
发表时间：
1999-10
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Emmanuel Valentin;F. Ghomashchi;Michael H. Gelb;M. Lazdunski;G. Lambeau
通讯作者：
Emmanuel Valentin;F. Ghomashchi;Michael H. Gelb;M. Lazdunski;G. Lambeau
人类 IIa 组分泌的磷脂酶 A2 对细胞膜的作用。
DOI：
10.1074/jbc.273.48.32142
发表时间：
1998
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Koduri,RS;Baker,SF;Snitko,Y;Han,SK;Cho,W;Wilton,DC;Gelb,MH
通讯作者：
Gelb,MH
影响因子：
7
作者：
P. Elsbach;Jerrold Weiss
通讯作者：
P. Elsbach;Jerrold Weiss
牛胰腺和响尾蛇毒液中磷脂酶 A2 晶体结构的比较。
DOI：
--
发表时间：
1985
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Renetseder,R;Brunie,S;Dijkstra,BW;Drenth,J;Sigler,PB
通讯作者：
Sigler,PB
影响因子：
13.8
作者：
Dennis, EA
通讯作者：
Dennis, EA