A Unique Loop Extension in the Serine Protease Domain of Haptoglobin Is Essential for CD163 Recognition of the Haptoglobin-Hemoglobin Complex

Nielsen, Marianne Jensby; Petersen, Steen V.; Jacobsen, Christian; Thirup, Søren; Enghild, Jan J.; Graversen, Jonas Heilskov; Moestrup, Søren K.

doi:10.1074/jbc.m605684200

Cited by 66 publications

(70 citation statements)

References 23 publications

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“…11,13 Nevertheless, the Hpr ␣-chains are thought to associate in a noncovalent manner to form (␣␤)-dimers. 36,52 Unlike what is observed for Hp, the Hpr amino-terminal signal peptide thought to direct secretion of the protein remains uncleaved. 38,42 This highly hydrophobic leader sequence may have a function in targeting Hpr to the lipoprotein complex TLF1 and to TLF2 that contains the amphipathic apoA-I protein.…”

mentioning

confidence: 71%

“…45,47 This surface-exposed loop is considerably enlarged in Hp (and Hpr) compared with the corresponding loop in serine proteases and plays a critical function in Hb scavenging. 52 The disulfide bridge pattern of the (␣␤)-unit of Hpr is homologous to that of Hp (Figure 2). 52 However, the inter-␣-chain disulfide bond is missing in Hpr because the cysteine 33 found Hp1 is replaced by a phenylalanine in Hpr.…”

Section: Structural Aspectsmentioning

confidence: 99%

“…52 The disulfide bridge pattern of the (␣␤)-unit of Hpr is homologous to that of Hp (Figure 2). 52 However, the inter-␣-chain disulfide bond is missing in Hpr because the cysteine 33 found Hp1 is replaced by a phenylalanine in Hpr. 11,13 Nevertheless, the Hpr ␣-chains are thought to associate in a noncovalent manner to form (␣␤)-dimers.…”

Section: Structural Aspectsmentioning

confidence: 99%

“…50,51 The main function of the Hp ␣-chains appears to be connection of (␣␤)-units to form dimers (Hp1-1 and Hp2-2 phenotypes) and multimers (Hp2-1 and Hp2-2 phenotypes), 2,52 whereas the interaction with other proteins, including Hb and CD163, is mediated by the larger and more accessible ␤-chain. 48,49,[52][53][54][55][56] The latter chain is generally more conserved between species than is the ␣-chain 57 and lacks the catalytic triad of genuine serine proteases. 47 Accordingly, no proteolytic activity has been assigned to Hp.…”

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confidence: 99%

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Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

Nielsen

Moestrup

2009

Blood

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135

109

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Haptoglobin, the haptoglobin-hemoglobin receptor CD163, and the heme oxygenase-1 are proteins with a well-established function in the clearance and metabolism of "free" hemoglobin released during intravascular hemolysis. This scavenging system counteracts the potentially harmful oxidative and NO-scavenging effects associated with "free" hemoglobin, and, furthermore, elicits an anti-inflammatory response. In the late primate evolution, haptoglobin variants with distinct functions have arisen, including haptoglobin polymers and the haptoglobin-related protein. The latter associates with a subspecies of high-density lipoprotein (HDL) particles playing a crucial role in the innate immunity against certain trypanosome parasites. Recent studies have elucidated this fairly sophisticated immune defense mechanism that takes advantage of a trypanosomal haptoglobin-hemoglobin receptor evolved to supply the parasite with heme. Because of the high resemblance between haptoglobin and haptoglobinrelated protein, the receptor also takes up the complex of hemoglobin and the HDL- IntroductionHaptoglobin (Hp), an abundant acute phase plasma glycoprotein of the ␣ 2 -globulin fraction, was initially reported in 1938 by Polonovski and Jayle to be a "plasma substance" that binds hemoglobin (Hb). 1 In agreement with this initial characterization and its designation as "haptoglobin" (Greek: haptein, "to bind" ϩ [hemo]globin), Hp has a well-established role in binding of "free" Hb released into the circulation during the process of intravascular hemolysis. By capturing the liberated Hb, Hp protects against toxic effects associated with Hb, and it facilitates Hb clearance through endocytosis by the macrophage scavenger receptor CD163. 2 Later studies of human and primate plasma revealed variant forms of Hp as well as the existence of an Hp-related protein (Hpr) that recently has been shown also to bind Hb. As highlighted in this review, novel functions of Hp depend on high-affinity interactions with Hb and lipoprotein and subsequent receptor recognition of the resulting complexes. Toxicity of hemoglobin released during intracellular hemolysisIntravascular hemolysis, which accounts for approximately 10% to 20% of total red blood cell destruction, 3 changes Hb from being an intracellular O 2 /CO 2 transporter to a highly toxic substance in plasma. This toxicity arises from the heme iron, which can react with endogenous hydrogen peroxide to produce free radicals, which in turn may cause severe oxidative tissue damage, 4 particularly in the kidney. 5 In addition to the oxidative toxicity of Hb, Hb is a potent scavenger of nitric oxide (NO), a signaling molecule that functions as a critical regulator of smooth muscle relaxation, endothelial adhesion molecule expression, and platelet activation and aggregation. 6,7 The reaction of Hb with NO is fast and irreversible, leading to the production of nitrate and methemoglobin. If allowed to occur, this Hbmediated consumption of vascular NO, referred to as NOscavenging, thus limits the bioavailabili...

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mentioning

confidence: 71%

Section: Structural Aspectsmentioning

confidence: 99%

Section: Structural Aspectsmentioning

confidence: 99%

mentioning

confidence: 99%

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Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

Nielsen

Moestrup

2009

Blood

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135

109

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“…6a). The interaction with CD163 involves two basic Hp-specific residues (Arg311 and Lys321) located in the loop 3 region 40 . These residues engage in a common type electrostatic and calcium-dependent binding to the scavenger receptor cysteinerich domains of CD163 (refs 41,42).…”

Section: Discussionmentioning

confidence: 99%

Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system

et al. 2014

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Sleeping sickness is caused by trypanosome parasites, which infect humans and livestock in Sub-Saharan Africa. Haem is an important growth factor for the parasites and is acquired from the host by receptor-mediated uptake of haptoglobin (Hp)-haemoglobin (Hb) complexes. The parasite Hp-Hb receptor (HpHbR) is also a target for a specialized innate immune defence executed by trypanosome-killing lipoprotein particles containing an Hp-related protein in complex with Hb. Here we report the structure of the multimeric complex between human Hp-Hb and Trypanosoma brucei brucei HpHbR. Two receptors forming kinked three-helical rods with small head regions bind to Hp and the b-subunits of Hb (bHb), with one receptor at each end of the dimeric Hp-Hb complex. The Hb b-subunit haem group directly associates with the receptors, which allows for sensing of haem-containing Hp-Hb. The HpHbR-binding region of Hp is conserved in Hp-related protein, indicating an identical recognition of Hp-Hb and trypanolytic particles by HpHbR in human plasma.

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Haptoglobin

Dalton¹,

Okemefuna²

2012

Production of Plasma Proteins for Therapeutic Use

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A Unique Loop Extension in the Serine Protease Domain of Haptoglobin Is Essential for CD163 Recognition of the Haptoglobin-Hemoglobin Complex

Cited by 66 publications

References 23 publications

Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system

Haptoglobin

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