Chemokine oligomerization and interactions with receptors and glycosaminoglycans: the role of structural dynamics in function - PubMed (original) (raw)

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Chemokine oligomerization and interactions with receptors and glycosaminoglycans: the role of structural dynamics in function

C L Salanga et al. Exp Cell Res. 2011.

Abstract

The first chemokine structure, that of IL-8/CXCL8, was determined in 1990. Since then, many chemokine structures have emerged. To the initial disappointment of structural biologists, the tertiary structures of these small proteins were found to be highly conserved. However, they have since proven to be much more interesting and diverse than originally expected. Somewhat like lego blocks, many chemokines oligomerize and there is significant diversity in their oligomeric forms and propensity to oligomerize. Chemokines not only interact with receptors where different oligomeric forms can induce different signaling responses, they also interact with glycosaminoglycans which can stabilize oligomers and other structures that would not otherwise form in solution. Although chemokine monomers and dimers yielded quickly to structure determination, structural information about larger chemokine oligomers, chemokines receptors, and complexes of chemokines with glycosaminoglycans and receptors has been more difficult to obtain, but recent breakthroughs suggest that this information will be forthcoming, especially with receptor structures. Equally important and challenging, will be efforts to correlate the structural information with function.

Copyright © 2011 Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1

Cartoon depicting the steps in cell migration where various chemokine structures and interactions may come into play. (A) Chemokines secreted into the extravascular space bind to GAGs and are transcytosed to the lumenal side of the endothelium where (B) they are presented on the endothelial surface to chemokine receptors on leukocytes in the blood. Many chemokines oligomerize on GAGs although there are other mechanisms for transport and presentation as described in the text (see Figure 7). (C) Chemokines bind to receptors, in some cases causing leukocyte arrest and firm adhesion, and there is some evidence that oligomeric forms of chemokines are involved in this process. (D) The monomeric forms of chemokines cause cell movement, which is now well-established. (E) Following extravasation, oligomerized chemokines may provide stop signals as possibly suggested by a disulfide locked dimer of SDF-1/CXCL12 or they may cause activation of leukocytes as demonstrated by RANTES/CCL5.

Figure 2

Figure 2

(A) Monomeric and (B) dimeric structures of MCP-1/CCL2 (PDB ID IDOM) [79]. (C) Dimer Structure of IL-8/CXCL8 (PDB ID 1IL8) [80]. (D) Non-canonical dimer of lymphotactin/XCL1 (PDB ID 2JP1). This non-canonical structure predominates at high temperature and low ionic strength (40°C, no salt) and binds to GAGs, whereas the canonical chemokine fold is stabilized by low temperature and high salt concentrations (10°C, 200 mM NaCl), and b inds the lymphotactin receptor [81]. (E) and (F) polymeric form of MIP-1α/CCL3 from the side and down the helical axis (PDB ID 2X69) [28].

Figure 3

Figure 3

Model of CXCR4 with SDF-1/CXCL12 depicting how chemokines were roughly hypothesized to interact with chemokine receptors until the recent crystal structure of CXCR4 was determined. The homology model of CXCR4 was generated based on the β2-adrenergic structure as a template; the conformation of the receptor N-terminus in complex with SDF-1 was inherited from the complex solution structure (PDB ID 2K05) [36]. Based on the results of mutagenesis studies, a restraint was imposed to ensure the spatial proximity of the CXCR4 transmembrane pocket residue, Glu288, with the N-terminal Lys1 of SDF-1. The model illustrates the so called “two-site model of receptor activation” involving two hypothetical interactions: the interaction of the NT signaling domain of the ligand with the receptor helical bundle, and the interaction of the “core domain” of the ligand with the N-terminus and extracellular loops of the receptor. In this model, SDF-1/CXCL12 is shown in pastel colors (blue, pink and red); K1 and K68 are the N and C-terminal residues of the ligand. The receptor is shown in orange where the N-terminus, ending in M1, is wrapped around the chemokine core domain. The figure was prepared using ICM software (

www.Molsoft.com

).

Figure 4

Figure 4

Structure of CXCR4 with the small molecule antagonist IT1t (left) and with the cyclic peptide CVX15 (right); both ligands are shown as yellow space filling models (PDB ID 3ODU and 3OEO) [61]. The receptor is colored according to electrostatic potential from red (negative) to blue (positive), in order to highlight the acidic nature of the binding pocket, which is shown in red. The structure of the receptor is clipped in order to visualize the pocket and the helices are shown as white ribbons. Only one subunit of the receptor dimer is illustrated. Figures were prepared using ICM software (

www.Molsoft.com

).

Figure 5

Figure 5

Structures of the CXCR4 dimer and the CXCL12 monomer and dimer (PDB ID 2J7Z) colored according to their electrostatic potential from red (negative) to blue (positive), in order to highlight the charge complementarity of these proteins. On the left, the CXCR4 structure is shown in two orientations -- on the top looking into the ligand binding pocket and on the bottom, from the side of the dimer. The top right shows the monomer and dimer of CXCL12; the bottom right shows the structure of the CXCR4 dimer, clipped, in order to illustrate the binding pocket and that multiple stoichiometries and orientations of the CXCL12:CXCR4 seem feasible, as described in the text (no orientations are implied in the figure). Figures were prepared using ICM software (

www.Molsoft.com

).

Figure 6

Figure 6

Structures of chemokine tetramers. (A) The MCP-1/CCL2 tetramer is illustrated in a space filling representation and (C) with a ribbon diagram, where each subunit is color coded differently (PDB ID 1DOL) [79]. (B) The MCP-1/CCL2 tetramer rotated by 90 degrees from the view in (A), highlighting the GAG-binding epitopes in light blue to illustrate how the GAG binding site wraps around the tetramer. (D) The tetramer of fraktalkine/CX3CL1 (PDB 1D 1F2L) [82]. (E) The tetramer of human IP-10/CXCL10 (PDB 1D 107Y) [83]. (F) The tetramer of murine IP-10/CXCL10 (PDB 1D 2R3Z) [84].

Figure 7

Figure 7

Different mechanisms for presentation of chemokines on GAGs to receptors on leukocytes. Note that it is not known whether chemokines interact simultaneously with GAGs and receptors as implied in the figure, or if the interactions are mutually exclusive. (A) Presentation of oligomerized chemokines on GAGs; this mechanism may be operative when the GAG and receptor binding sites overlap as in the case of MCP-1/CCL2 and many other chemokines. While only an hypothesis, oligomerization would permit binding of some chemokine subunits to the GAG while other subunits would be available for receptor binding. (B) Some chemokines like SDF-1γ, have long unstructured C-terminal tails that can be used as GAG “hooks”; in this case the GAG binding and receptor binding epitopes may be independent allowing for simultaneous interaction of chemokines with GAGs and receptors. (C) Although not discussed in the text, it is worth noting that non-signaling seven transmembrane receptors can act as presentation molecules; for example, CCRL2 acts as presentation scaffold for the chemoattractant chemerin [85]. (D) Furthermore, fractalkine/CX3CL1 and CXCL16 are attached to long mucin-like stalks which are tethered to the membrane by single transmembrane helixes. In addition to providing a presentation mechanism for these chemokines, the tethered chemokines act directly as adhesion molecules [86].

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