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首页> 外文期刊>Biochemistry >Caveolin-1 Is a Competitive Inhibitor of Heme Oxygenase-1 (HO-1) with Heme: Identification of a Minimum Sequence in Caveolin-1 for Binding to HO-1
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Caveolin-1 Is a Competitive Inhibitor of Heme Oxygenase-1 (HO-1) with Heme: Identification of a Minimum Sequence in Caveolin-1 for Binding to HO-1

机译：Caveolin-1是与血红素竞争的血红素加氧酶-1（HO-1）的抑制剂：Caveolin-1中与HO-1结合的最小序列的鉴定

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摘要

Heme oxygenase (HO) catalyzes the O2-dependent degradation of heme to biliverdin IXα, carbon monoxide (CO), and free ferrous iron through a multistep mechanism. Electrons required for HO catalysis in mammals are provided by NADPH–cytochrome P450 reductase. Recently, Kim et al. reported for the first time that HO, especially inducible HO-1, appears in caveolae and showed that caveolin-1, a principal isoform of the caveolin family, physically interacts with HO-1 [Jung, N. H. et al. (2003) IUBMB Life55, 525−532; Kim, H. P. et al. (2004) FASEB J.18, 1080–1089]. In the present study, we confirmed by immunoprecipitation experiments that rat HO-1 and rat caveolin-1 (residues 1–101) directly interact with each other and that the HO-1 activity is inhibited by caveolin-1 (1–101). The 82–101 residues of caveolin-1 (CAV(82–101)), called the caveolin scaffolding domain, play essential roles in caveolin-related protein–protein interactions. The HO-1 activity is also inhibited by CAV(82–101) in a competitive manner with hemin, and a hemin titration experiment showed that CAV(82–101) interferes with hemin binding to HO-1. The enzyme kinetics and surface plasmon resonance experiments gave comparable Ki and KD values of 5.2 and 1.0 μM for CAV(82–101), respectively, with respect to the interaction with HO-1. These observations indicated that CAV(82–101) and hemin share a common binding site within the HO-1 protein. The identified caveolin binding motif (FLLNIELF) of rat HO-1 is incomplete compared to the proposed consensus sequence. The affinity between HO-1 and CAV(82–101), however, was almost completely or remarkably eliminated by replacement of Phe207 and/or Phe214 with Ala, indicating that HO-1 binds to caveolin-1 via this motif. Among the peptide fragments derived from CAV(82–101), i.e., CAV(82–91), CAV(87–96), CAV(92–101), and CAV(97–101), CAV(92–101) and CAV(97–101) are able to inhibit the HO-1 activity to a similar extent; thus, the five-amino acid sequence (residues 97–101) is considered to be a minimum sequence for binding to HO-1.
机译：血红素加氧酶（HO）通过多步机制催化O 2 依赖的血红素降解为联生物素IXα，一氧化碳（CO）和游离亚铁。 NADPH–细胞色素P450还原酶提供哺乳动物HO催化所需的电子。最近，金等。首次报道HO，特别是可诱导的HO-1出现在caveolae中，并表明caveolin-1是caveolin家族的主要同工型，与HO-1发生了物理相互作用[Jung，N. H.等。 （2003）IUBMB Life55，525-532; Kim，H.P.等。 （2004）FASEB J.18，1080-1089]。在本研究中，我们通过免疫沉淀实验证实了大鼠HO-1和大鼠小窝蛋白1（残基1–101）直接相互作用，并且小窝蛋白1（1–101）抑制了HO-1的活性。小窝蛋白1（CAV（82–101））的82–101个残基，称为小窝蛋白支架结构域，在小窝蛋白相关的蛋白相互作用中起着至关重要的作用。 CAV（82–101）与血红素竞争性地抑制了HO-1的活性，而血红素的滴定实验表明CAV（82–101）干扰了血红素与HO-1的结合。酶动力学和表面等离振子共振实验得出CAV（82–101）的K i 和K D 分别具有5.2和1.0μM的相互作用值与HO-1。这些观察结果表明，CAV（82-101）和血红素在HO-1蛋白内有一个共同的结合位点。与提出的共有序列相比，已鉴定的大鼠HO-1的小窝蛋白结合基序（FLLNIELF）不完整。然而，HO-1和CAV（82–101）之间的亲和力几乎被Ala取代Phe 207 和/或Phe 214 完全或显着消除了，这表明HO-1通过该基序与小窝蛋白1结合。在源自CAV（82-101）的肽片段中，即CAV（82-91），CAV（87-96），CAV（92-101）和CAV（97-101），CAV（92-101）和CAV（97-101）能够以相似的程度抑制HO-1的活性。因此，五氨基酸序列（残基97-101）被认为是与HO-1结合的最小序列。

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