Structural Insights into the Interaction between a Potent Anti-inflammatory Protein, Viral CC Chemokine Inhibitor (vCCI), and the Human CC Chemokine, Eotaxin-1

Kuo, Nai-Wei; Gao, Yong-Guang; Schill, Megan S; Isern, Nancy G.; Dupureur, Cynthia M.; LiWang, Patricia J.

doi:10.1074/jbc.m113.538991

Cited by 15 publications

(32 citation statements)

References 70 publications

(92 reference statements)

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“…chemokine inhibitor (vCCI), which binds tightly to numerous CC chemokines, thereby inhibiting their receptor interactions. Recent biochemical and structural studies have shown that vCCI interacts with a surface of CC chemokines that substantially overlaps the region shown here to interact with the receptor N terminus and that the same positively charged residues of the chemokines contribute to stabilization of the vCCI interactions (Beck et al, 2001;Kuo et al, 2014;Seet et al, 2001;Zhang et al, 2006).…”

Section: Implications For Receptor Recognition By Other CC Chemokinesmentioning

confidence: 87%

Structural Basis of Receptor Sulfotyrosine Recognition by a CC Chemokine: The N-Terminal Region of CCR3 Bound to CCL11/Eotaxin-1

et al. 2014

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Trafficking of leukocytes in immune surveillance and inflammatory responses is activated by chemokines engaging their receptors. Sulfation of tyrosine residues in peptides derived from the eosinophil chemokine receptor CCR3 dramatically enhances binding to cognate chemokines. We report the structural basis of this recognition and affinity enhancement. We describe the structure of a CC chemokine (CCL11/eotaxin-1) bound to a fragment of a chemokine receptor: residues 8–23 of CCR3, including two sulfotyrosine residues. We also show that intact CCR3 is sulfated and sulfation enhances receptor activity. The CCR3 sulfotyrosine residues form hydrophobic, salt bridge and cation-p interactions with residues that are highly conserved in CC chemokines. However, the orientation of the chemokine relative to the receptor N terminus differs substantially from those observed for two CXC chemokines, suggesting that initial binding of the receptor sulfotyrosine residues guides subsequent steps in receptor activation, thereby influencing the receptor conformational changes and signaling.

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Section: Implications For Receptor Recognition By Other CC Chemokinesmentioning

confidence: 87%

Structural Basis of Receptor Sulfotyrosine Recognition by a CC Chemokine: The N-Terminal Region of CCR3 Bound to CCL11/Eotaxin-1

et al. 2014

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“…Recently, a soluble poxvirus‐encoded protein, named viral CC chemokine inhibitor, was shown to bind through electrostatic interactions with CCL11. However, the functional consequences thereof were not investigated .…”

Section: Discussionmentioning

confidence: 99%

Osteopontin binds and modulates functions of eosinophil‐recruiting chemokines

Gela

Kasetty

Mörgelin

et al. 2015

Allergy

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“…One of the most potent inhibitors of chemokine action is the poxvirus-encoded protein vCCI (viral CC chemokine inhibitor; also called 35K). This approximately 240 amino acid protein binds 80 CC-chemokines across several species, about 20 of which have nanomolar affinity to this inhibitor [ 10 , 11 ]. The protein sequence across several poxviruses shows high identity, and the structures from cowpox [ 12 ], rabbitpox [ 13 ], and mousepox [ 14 ] reveal a beta sandwich with a binding face containing several key negatively charged amino acids, as well as a long acidic loop between beta strands 2 and 3.…”

Section: Introductionmentioning

confidence: 99%

“…Mutagenesis of vCCI/35K by others, in vitro and in vivo, has confirmed the importance of several of the residues suggested by the structure, including E143 and the acidic loop [ 14 , 15 ]. Mutagenesis studies on the chemokines themselves have also been carried out by us and others and indicate that several evolutionarily conserved, positively charged residues are important for binding to vCCI/35K [ 11 , 16 , 17 ]. In our work, with a variety of eotaxin mutants (CCL11 [ 11 ]), we showed that eotaxin’s binding to vCCI was dependent on the presence of several basic residues in the chemokine.…”

Section: Introductionmentioning

confidence: 99%

Biophysical and Computational Studies of the vCCI:vMIP-II Complex

Nguyen

Kuo

Showalter

et al. 2017

IJMS

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Certain viruses have the ability to subvert the mammalian immune response, including interference in the chemokine system. Poxviruses produce the chemokine binding protein vCCI (viral CC chemokine inhibitor; also called 35K), which tightly binds to CC chemokines. To facilitate the study of vCCI, we first provide a protocol to produce folded vCCI from Escherichia coli (E. coli.) It is shown here that vCCI binds with unusually high affinity to viral Macrophage Inflammatory Protein-II (vMIP-II), a chemokine analog produced by the virus, human herpesvirus 8 (HHV-8). Fluorescence anisotropy was used to investigate the vCCI:vMIP-II complex and shows that vCCI binds to vMIP-II with a higher affinity than most other chemokines, having a Kd of 0.06 ± 0.006 nM. Nuclear magnetic resonance (NMR) chemical shift perturbation experiments indicate that key amino acids used for binding in the complex are similar to those found in previous work. Molecular dynamics were then used to compare the vCCI:vMIP-II complex with the known vCCI:Macrophage Inflammatory Protein-1β/CC-Chemokine Ligand 4 (MIP-1β/CCL4) complex. The simulations show key interactions, such as those between E143 and D75 in vCCI/35K and R18 in vMIP-II. Further, in a comparison of 1 μs molecular dynamics (MD) trajectories, vMIP-II shows more overall surface binding to vCCI than does the chemokine MIP-1β. vMIP-II maintains unique contacts at its N-terminus to vCCI that are not made by MIP-1β, and vMIP-II also makes more contacts with the vCCI flexible acidic loop (located between the second and third beta strands) than does MIP-1β. These studies provide evidence for the basis of the tight vCCI:vMIP-II interaction while elucidating the vCCI:MIP-1β interaction, and allow insight into the structure of proteins that are capable of broadly subverting the mammalian immune system.

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Structural Insights into the Interaction between a Potent Anti-inflammatory Protein, Viral CC Chemokine Inhibitor (vCCI), and the Human CC Chemokine, Eotaxin-1

Cited by 15 publications

References 70 publications

Structural Basis of Receptor Sulfotyrosine Recognition by a CC Chemokine: The N-Terminal Region of CCR3 Bound to CCL11/Eotaxin-1

Structural Basis of Receptor Sulfotyrosine Recognition by a CC Chemokine: The N-Terminal Region of CCR3 Bound to CCL11/Eotaxin-1

Osteopontin binds and modulates functions of eosinophil‐recruiting chemokines

Biophysical and Computational Studies of the vCCI:vMIP-II Complex

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