Okroj Marcin, Mark Linda, Stokowska Anna, Wong Scott W, Rose Nicola, Blackbourn David J, Villoutreix Bruno O, Spiller O Brad, Blom Anna M
Department of Laboratory Medicine, Lund University, University Hospital Malmo¨, Malmo¨ S-20502, Sweden, the Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon 97006, the National Institute for Biological Standards and Control, Herts EN6 3QG, United Kingdom, the Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham B15 2TT, United Kingdom, INSERM MTi, University Paris Diderot, Paris 75013, France, and the Department of Child Health, Cardiff University, Wales School of Medicine, Cardiff CF14 4XN, United Kingdom.
Department of Laboratory Medicine, Lund University, University Hospital Malmo¨, Malmo¨ S-20502, Sweden, the Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon 97006, the National Institute for Biological Standards and Control, Herts EN6 3QG, United Kingdom, the Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham B15 2TT, United Kingdom, INSERM MTi, University Paris Diderot, Paris 75013, France, and the Department of Child Health, Cardiff University, Wales School of Medicine, Cardiff CF14 4XN, United Kingdom.
J Biol Chem. 2009 Jan 2;284(1):505-514. doi: 10.1074/jbc.M806669200. Epub 2008 Nov 6.
Rhesus rhadinovirus (RRV) is currently the closest known, fully sequenced homolog of human Kaposi sarcoma-associated herpesvirus. Both these viruses encode complement inhibitors as follows: Kaposi sarcoma-associated herpesvirus-complement control protein (KCP) and RRV-complement control protein (RCP). Previously we characterized in detail the functional properties of KCP as a complement inhibitor. Here, we performed comparative analyses for two variants of RCP protein, encoded by RRV strains H26-95 and 17577. Both RCP variants and KCP inhibited human and rhesus complement when tested in hemolytic assays measuring all steps of activation via the classical and the alternative pathway. RCP variants from both RRV strains supported C3b and C4b degradation by factor I and decay acceleration of the classical C3 convertase, similar to KCP. Additionally, the 17577 RCP variant accelerated decay of the alternative C3 convertase, which was not seen for KCP. In contrast to KCP, RCP showed no affinity to heparin and is the first described complement inhibitor in which the binding site for C3b/C4b does not interact with heparin. Molecular modeling shows a structural disruption in the region of RCP that corresponds to the KCP-heparin-binding site. This makes RRV a superior model for future in vivo investigations of complement evasion, as RCP does not play a supportive role in viral attachment as KCP does.
恒河猴疱疹病毒（RRV）是目前已知与人类卡波西肉瘤相关疱疹病毒最接近的、已完成全序列测定的同源物。这两种病毒都编码补体抑制剂，具体如下：卡波西肉瘤相关疱疹病毒补体控制蛋白（KCP）和RRV补体控制蛋白（RCP）。此前我们详细描述了KCP作为补体抑制剂的功能特性。在此，我们对由RRV毒株H26 - 95和17577编码的RCP蛋白的两种变体进行了比较分析。在通过经典途径和替代途径测量激活所有步骤的溶血试验中进行测试时，两种RCP变体和KCP均能抑制人和恒河猴补体。来自两种RRV毒株的RCP变体都支持I因子介导的C3b和C4b降解以及经典C3转化酶的衰变加速，这与KCP类似。此外，17577 RCP变体加速了替代C3转化酶的衰变，而KCP则没有这种现象。与KCP不同，RCP对肝素没有亲和力，并且是首个被描述的补体抑制剂，其C3b/C4b结合位点不与肝素相互作用。分子建模显示RCP中对应于KCP - 肝素结合位点的区域存在结构破坏。这使得RRV成为未来补体逃逸体内研究的一个更优模型，因为RCP不像KCP那样在病毒附着中起支持作用。
