de la Morena-Barrio María, Sandoval Edna, Llamas Pilar, Wypasek Ewa, Toderici Mara, Navarro-Fernández José, Rodríguez-Alen Agustín, Revilla Nuria, López-Gálvez Raquel, Miñano Antonia, Padilla José, de la Morena-Barrio Belén, Cuesta Jorge, Corral Javier, Vicente Vicente
Dr. Javier Corral, University of Murcia, Centro Regional de Hemodonación, Calle Ronda de Garay s/n. Murcia 30003, Spain, Tel.: +34 968341990, Fax: +34 968261914, E-mail:
Thromb Haemost. 2017 May 3;117(5):880-888. doi: 10.1160/TH16-11-0866. Epub 2017 Feb 23.
Antithrombin is an anticoagulant serpin that efficiently inhibits multiple procoagulant proteases. The cost for the structural flexibility required for this function is the vulnerability to mutations that impact its folding pathway. Most conformational mutations identified in serpins cause polymerisation. Only three mutations in SERPINC1 affecting two residues have been found to favour transformation to the latent conformation of antithrombin, another hyperstable non-anticoagulant form with strong antiangiogenic activity that constitutes 3 % of plasma antithrombin in healthy subjects. The analysis of latent antithrombin in 141 unrelated patients with antithrombin deficiency carrying 89 different SERPINC1 mutations identified four cases with higher levels than that of controls: p.Pro439Thr, p.Pro461Ser, p.Met283Val, and p.His401Tyr, the last also with circulating polymers. Heating of plasma at 42ºC exacerbated the transformation to the latent conformation in p.Pro439Thr and p.Pro461Ser. The conformational effect of p.Met283Val, the mutation associated with the highest levels of latent antithrombin detected in four members of a family, was verified in a recombinant model. Antithrombin deficiency in these cases should be classified as pleiotropic based on the impaired reactivity and low heparin affinity of the variant. Despite high levels of latent antithrombin (up to 80 µg/ml in p.Met283Val carriers), no vascular defects were described in carriers of these mutations. In conclusion, our study identifies new residues involved in the structural stability of antithrombin (and potentially of all serpins). High levels of endogenous latent antithrombin seem to play a minor antiangiogenic effect. Finally, pleiotropic deficiencies may be caused by mutations inducing transformation to the latent conformation.
抗凝血酶是一种抗凝丝氨酸蛋白酶抑制剂，可有效抑制多种促凝血蛋白酶。该功能所需的结构灵活性的代价是易受影响其折叠途径的突变影响。在丝氨酸蛋白酶抑制剂中鉴定出的大多数构象突变会导致聚合。在SERPINC1中，仅发现影响两个残基的三个突变有利于转化为抗凝血酶的潜在构象，抗凝血酶是另一种具有强抗血管生成活性的超稳定非抗凝形式，在健康受试者中占血浆抗凝血酶的3%。对141名携带89种不同SERPINC1突变的抗凝血酶缺乏症无关患者的潜在抗凝血酶分析发现，有4例患者的潜在抗凝血酶水平高于对照组：p.Pro439Thr、p.Pro461Ser、p.Met283Val和p.His401Tyr，最后一例还伴有循环聚合物。在42℃加热血浆会加剧p.Pro439Thr和p.Pro461Ser向潜在构象的转化。在一个重组模型中验证了p.Met283Val的构象效应，该突变与一个家族的四名成员中检测到的最高水平的潜在抗凝血酶相关。基于变体的反应性受损和低肝素亲和力，这些病例中的抗凝血酶缺乏应归类为多效性。尽管潜在抗凝血酶水平很高（p.Met283Val携带者中高达80μg/ml），但这些突变携带者中未描述血管缺陷。总之，我们的研究确定了参与抗凝血酶（可能还有所有丝氨酸蛋白酶抑制剂）结构稳定性的新残基。高水平的内源性潜在抗凝血酶似乎具有轻微的抗血管生成作用。最后，多效性缺陷可能由诱导转化为潜在构象的突变引起。
