Receptor-binding conformation of the ?ELR? motif of IL-8: X-ray structure of the L5C/H33C variant at 2.35 ? resolution

Gerber, Nancy Counts; Lowman, Henry B.; Artis, Dean R.

doi:10.1002/(sici)1097-0134(20000301)38:4<361::aid-prot2>3.0.co;2-0

Cited by 21 publications

(9 citation statements)

References 24 publications

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“…Analysis of the CSI plot in Fig. 2a is consistent with the locations of the secondary structure elements established in previous studies of IL-8 (Clore et al 1990; Baldwin et al 1991; Rajarathnam et al 1995; Eigenbrot et al 1997; Gerber et al 2000). Notably, monomeric IL-8(1–66) has three β-strands in the middle of the sequence and an α-helix located at the C-terminus.…”

Section: Resultssupporting

confidence: 87%

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Structure of monomeric Interleukin-8 and its interactions with the N-terminal Binding Site-I of CXCR1 by solution NMR spectroscopy

et al. 2017

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The structure of monomeric human chemokine IL-8 (residues 1–66) was determined in aqueous solution by NMR spectroscopy. The structure of the monomer is similar to that of each subunit in the dimeric full-length protein (residues 1–72), with the main differences being the location of the N-loop (residues 10–22) relative to the C-terminal α-helix and the position of the side chain of phenylalanine 65 near the truncated dimerization interface (residues 67–72). NMR was used to analyze the interactions of monomeric IL-8 (1–66) with ND-CXCR1 (residues 1–38), a soluble polypeptide corresponding to the N-terminal portion of the ligand binding site (Binding Site-I) of the chemokine receptor CXCR1 in aqueous solution, and with 1TM-CXCR1 (residues 1–72), a membrane-associated polypeptide that includes the same N-terminal portion of the binding site, the first trans-membrane helix, and the first intracellular loop of the receptor in nanodiscs. The presence of neither the first transmembrane helix of the receptor nor the lipid bilayer significantly affected the interactions of IL-8 with Binding Site-I of CXCR1.

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Section: Resultssupporting

confidence: 87%

“…The structure of the wild-type IL-8 dimer was first determined by solution NMR and X-ray crystallography (Clore et al 1990; Baldwin et al 1991). Subsequently, its structure has been characterized under a range of conditions and with a number of mutations (Rajarathnam et al 1995; Eigenbrot et al 1997; Gerber et al 2000). …”

Section: Introductionmentioning

confidence: 99%

Structure of monomeric Interleukin-8 and its interactions with the N-terminal Binding Site-I of CXCR1 by solution NMR spectroscopy

et al. 2017

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“…VOL. 26,2006 DEK IS A SECRETED CHEMOTACTIC FACTOR 9493 CXCR2 and CXCR1 receptors (18,53,68). Further studies will assess whether DEK's chemoattractant function is mediated through specific interaction with CXCR2 and/or CXCR1 receptors.…”

Section: Discussionmentioning

confidence: 99%

The DEK Nuclear Autoantigen Is a Secreted Chemotactic Factor

Mor‐Vaknin

Punturieri

Sitwala

et al. 2006

Molecular and Cellular Biology

134

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The nuclear DNA-binding protein DEK is an autoantigen that has been implicated in the regulation of transcription, chromatin architecture, and mRNA processing. We demonstrate here that DEK is actively secreted by macrophages and is also found in synovial fluid samples from patients with juvenile arthritis. Secretion of DEK is modulated by casein kinase 2, stimulated by interleukin-8, and inhibited by dexamethasone and cyclosporine A, consistent with a role as a proinflammatory molecule. DEK is secreted in both a free form and in exosomes, vesicular structures in which transcription-modulating factors such as DEK have not previously been found. Furthermore, DEK functions as a chemotactic factor, attracting neutrophils, CD8؉ T lymphocytes, and natural killer cells. Therefore, the DEK autoantigen, previously described as a strictly nuclear protein, is secreted and can act as an extracellular chemoattractant, suggesting a direct role for DEK in inflammation.DEK is a mammalian oncoprotein and putative autoantigen whose primary biological function has not been previously elucidated, despite literature linking it to the regulation of transcription, chromatin architecture, and mRNA processing (1,2,11,15,16,24,35,51,65). The DEK protein is widely conserved among species and is transcribed at high levels, especially in hematopoietically derived cells (14,(62)(63)(64). DEK was first characterized as part of the protein product of the DEK-CAN fusion oncogene, resulting from a t(6;9) translocation found in a subset of patients with acute myelogenous leukemia (64). DEK is overexpressed in several different malignancies, including melanoma, hepatocellular carcinoma, glioblastoma, retinoblastoma, bladder cancer, T-cell large granular lymphocyte leukemia, and acute myelogenous leukemia independent of the t(6;9) translocation (7,10,19,20,29,30,32,39,64). Although DEK has previously been described as a strictly nuclear protein, DEK autoreactivity has been identified as a major component of the autoantibody profile in patients with juvenile idiopathic arthritis (JIA) and is also seen in patients with other autoimmune diseases (8,21,38,49,54,55). In the studies presented in this paper, we show that the nuclear protein DEK can be actively secreted by inflammatory cells, is found in synovial fluid samples from JIA patients, and can function as a chemoattractant for inflammatory cells, suggesting a potential role for DEK in immunity and/or autoimmunity. MATERIALS AND METHODSCell preparation. Monocyte-derived macrophages (MDM) were prepared as previously described (31). Briefly, heparinized venous blood samples were collected from healthy volunteers following a protocol approved by the institutional review board, and peripheral blood mononuclear cells were separated by FicollHypaque (Amersham Pharmacia Biotech AB, Uppsala, Sweden) density gradient centrifugation. MDM were purified by adherence to plastic for 2 h at 37°C at a concentration of 5 ϫ 10 5 /ml. Adherent cells were consistently Ͼ90% monocytes (31). Adherence-purified human mon...

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“…This substitution was chosen because IL-8, a homologous member of CXC chemokine family, forms dimers but is not known to form tetramers or higher-ordered structures. 35 Additionally, a double mutation was constructed in which both the Glu 28 and Lys 50 residues in PF4 were replaced with those of IL-8, ie, PF4-E 28 R-K 50 E, that should theoretically restore the ability to form an ionic bond and thereby a PF4 tetramer.…”

Section: Tetrameric Structure Of Pf4 Is Critical To Form Ulcsmentioning

confidence: 99%

Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia

Rauova

Poncz

McKenzie

et al. 2005

Blood

275

306

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Heparin-induced thrombocytopenia and thrombosis (HITT) is a severe complication of heparin therapy caused by antibodies to complexes between unfractionated heparin (UFH) and platelet factor 4 (PF4) that form over a narrow molar range of reactants and initiate antibody-induced platelet activation. We observed that UFH and tetrameric PF4 formed ultralarge (> 670 kDa) complexes (ULCs) only over a narrow molar range with an optimal ratio of PF4 to heparin of approximately 1:1. These ULCs were stable and visible by electron microscopy, but they could be dissociated into smaller complexes upon addition of heparin. ULCs formed inefficiently when PF4 was incubated with low-molecular-weight heparin, and none formed with the pentasaccharide fondaparinux sodium. In addition, mutation studies showed that formation of ULCs depended on the presence of PF4 tetramers. The ULCs were more reactive as determined by their capacity to bind to a HITTlike monoclonal antibody and showed greater capacity to promote platelet activation in an antibody-and Fc␥RIIA-dependent manner than were the smaller complexes. The capacity of PF4 to form ULCs composed of multiple PF4 tetramers arrayed in a lattice with several molecules of UFH may play a fundamental role in autoantibody formation, antibody-dependent platelet activation, and the propensity for thrombosis in patients with HITT.

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Receptor-binding conformation of the ?ELR? motif of IL-8: X-ray structure of the L5C/H33C variant at 2.35 ? resolution

Cited by 21 publications

References 24 publications

Structure of monomeric Interleukin-8 and its interactions with the N-terminal Binding Site-I of CXCR1 by solution NMR spectroscopy

Structure of monomeric Interleukin-8 and its interactions with the N-terminal Binding Site-I of CXCR1 by solution NMR spectroscopy

The DEK Nuclear Autoantigen Is a Secreted Chemotactic Factor

Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia

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