Aggregation of the chemokine MIP-1 alpha is a dynamic and reversible phenomenon. Biochemical and biological analyses.

Graham, Gerard J.; Mackenzie, J. S.; Lowe, Scott W.; Tsang, Monica; Weatherbee, James A.; Issacson, A; Medicherla, Jagannadham V.; Fang, Fa; Wilkinson, P. C.; Pragnell, Ian B.

doi:10.1016/s0021-9258(17)37641-x

Cited by 59 publications

(13 citation statements)

References 31 publications

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“…Recently, IL-8 mutants with disrupted dimer interfaces that are monomeric up to millimolar concentrations have been prepared and found to be capable of binding, attracting, and activating neutrophils (Rajarathnam et al, 1994). Similarly, mutational studies with MIPla have identified proteins that are monomeric at physiological concentrations and equipotent to wild-type protein in terms of stem cell inhibition and induction of monocyte shape change (Graham et al, 1994). These studies indicate that, for some chemokine functions, the quaternary structure is not important and that useful insight into the structural features required for receptor binding and stimulation may be obtained by comparison of the monomer structures (with the caveat that the determined structure may be influenced by the quaternary interactions).…”

Section: Discussionmentioning

confidence: 99%

“…The different quaternary structures of IL-8 and MIP-l/j have been attributed to hydrophobic residues at the Nterminus of C-C chemokines or in strand /f 1 of C-X-C chemokines (Coveil et al, 1994). The activity of designed monomeric forms of IL-8 and MIP-la (Graham et al" 1994;Rajarathnam et al, 1994) and analytical ultra centrifugation studies of IL-8, MCP-1, and 1-309 (Burrows et al, 1994;Paolini et al, 1994) suggest that the monomeric form of all chemokines may be functionally important at the low physiological concentrations expected in a biological milieu.…”

Section: Discussionmentioning

confidence: 99%

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Proton NMR Assignments and Solution Conformation of RANTES, a Chemokine of the C-C Type

Skelton¹,

Aspiras²,

Ogez³

et al. 1995

Biochemistry

155

196

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1H NMR has been used to investigate the structural properties of RANTES, a protein from the C-C branch of the chemotactic cytokine family that has a strong chemoattractive effect on monocytes, lymphocytes, and eosinophils. Titration of pH from 5.0 to 2.5 indicates that RANTES is extensively aggregated in solution above pH 4.0. At pH 3.7 the protein is mostly dimeric, although this species does dissociate to the monomer with a Kd of 35 microM. NMR data have been acquired and resonance assignments made for the dimeric species. Structures of the dimer have been generated by distance geometry and simulated annealing calculations that utilized 1956 intramolecular distance restraints, 120 intermolecular distance restraints, 164 dihedral angle restraints, and 68 restraints enforcing 34 hydrogen bonds (17.0 restraints per residue). The structure is well-defined (average root mean square deviation from the average structure of 0.38 +/- 0.06 and 0.53 +/- 0.12 A for backbone heavy atoms of residues 4-66 of the monomer and dimer, respectively). Each monomer consists of a C-terminal alpha-helix packing against a three-stranded antiparallel beta-sheet and two short N-terminal beta-strands; dimerization occurs between the N-terminal regions of each monomer. This quaternary structure is very different from that of the C-X-C chemokines such as interleukin-8 and melanoma growth stimulatory activity but similar to that found for the C-C chemokine macrophage inflammatory factor 1 beta. Distinct structural differences between RANTES and other chemokines at both the tertiary and quaternary level are discussed with regard to the distinct biological functions of the C-C and C-X-C members of this protein family.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Proton NMR Assignments and Solution Conformation of RANTES, a Chemokine of the C-C Type

Skelton¹,

Aspiras²,

Ogez³

et al. 1995

Biochemistry

155

196

View full text Add to dashboard Cite

show abstract

“…The present findings may also apply to other members of the chemokine family. It was recently reported that introduction of three carboxy-terminal mutations into MIP-la rendered it monomeric at concentrations where wild-type MIPla is highly self-associated, yet there was no change in biological activity (Graham et al, 1994). Furthermore, the monomer conformation of self-associated forms of chemokines appears to be conserved for IL-8, PF4, and MIP-1 ß (Baldwin et al, 1991;Charles et al, 1989;Clore et al, 1990;Lodi et al, 1994), despite differences in the way that IL-8 and PF4 associate compared to MIP-ljS.…”

Section: Discussionmentioning

confidence: 99%

“…NMR and X-ray crystallography show that IL-8 is a homodimer (Baldwin et al, 1991;Clore et al, 1990) and reveal a structure related to platelet factor-4, another member of the chemokine family, which is tetrameric (Charles et al, 1989). Other members of the chemokine family, such as MIP-ljS (Lodi et al, 1994), are also structurally similar and tend to self-associate (Graham et al, 1994).…”

mentioning

confidence: 97%

Determination of the monomer-dimer equilibrium of interleukin-8 reveals it is a monomer at physiological concentrations

Burrows¹,

Doyle²,

Murphy³

et al. 1994

Biochemistry

156

124

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Interleukin-8 has been shown by X-ray crystallography and NMR to be a homodimer, suggesting that this is the form which binds to its receptor. Here we measure, for the first time, the monomer-dimer equilibrium of interleukin-8 using analytical ultracentrifugation and titration microcalorimetry and find that it dissociates readily to monomers with an equilibrium dissociation constant of 18 +/- 6 microM at 37 degrees C. The present findings suggest that the monomer is the form which binds to the receptor. Comparison of experimental and structure-based calculated thermodynamics of interleukin-8 dimerization argues for limited subunit conformational changes upon dissociation to monomer.

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“…Does Chemokine Oligomerization Enable Presentation of Chemokines to Receptors in a GAG-Bound Form? It has been known for years that most chemokines reversibly oligomerize in solution [21][22][23]. Chemokine oligomers are also stabilized by their interaction with GAGs, and GAG interactions can promote higher order chemokine oligomerization [6,24].…”

Section: Do Gags and Receptors Compete For The Same Binding Site On Chemokines?mentioning

confidence: 99%

Leukocyte Adhesion: Reconceptualizing Chemokine Presentation by Glycosaminoglycans

Graham

Handel

Proudfoot

2019

Trends in Immunology

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Recruitment of immune cells from the vasculature relies on the presentation of glycosaminoglycan-bound chemokines on the luminal side of vascular endothelial cells. However, the current model of chemokine-glycosaminoglycan interactions, and its implications for receptor interactions, remains poorly developed. We propose a refined 'Chemokine Cloud' model, arguing that chemokines are not presented to leukocytes bound to glycosaminoglycans, but rather, in solution while sequestered within the hydrated glycocalyx. We posit that glycosaminoglycans provide an immobilized chemokine depot maintaining a 'cloud' of 'solution-phase' chemokines within the glycocalyx, and that it is this soluble form of any given chemokine that interacts with leukocyte-bound receptors. Our proposition clarifies certain anomalies associated with the current model of chemokineglycosaminoglycan interactions, with implications for the design of blockers of chemokine function. Chemokine-Receptor Interactions in Transendothelial Cell Migration HighlightsRecent chemokine receptor structures indicate that oligomerization of chemokines, which is important for chemokine-GAG interactions, is incompatible with receptor binding.Receptor-ligand structures are incompatible with a model of direct presentation of ligand bound to GAGs.Recent in vivo data suggest that antichemokine antibodies targeting chemokines in 'soluble phase', rather than attached to GAGs, can be more effective in ameliorating certain inflammatory conditions.

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Aggregation of the chemokine MIP-1 alpha is a dynamic and reversible phenomenon. Biochemical and biological analyses.

Cited by 59 publications

References 31 publications

Proton NMR Assignments and Solution Conformation of RANTES, a Chemokine of the C-C Type

Proton NMR Assignments and Solution Conformation of RANTES, a Chemokine of the C-C Type

Determination of the monomer-dimer equilibrium of interleukin-8 reveals it is a monomer at physiological concentrations

Leukocyte Adhesion: Reconceptualizing Chemokine Presentation by Glycosaminoglycans

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