Structural basis of native CXCL7 monomer binding to CXCR2 receptor N-domain and glycosaminoglycan heparin

Aaron J. Brown, Krishna Mohan Sepuru, Krishna Rajarathnam

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

CXCL7, a chemokine highly expressed in platelets, orchestrates neutrophil recruitment during thrombosis and related pathophysiological processes by interacting with CXCR2 receptor and sulfated glycosaminoglycans (GAG). CXCL7 exists as monomers and dimers, and dimerization (~50 µM) and CXCR2 binding (~10 nM) constants indicate that CXCL7 is a potent agonist as a monomer. Currently, nothing is known regarding the structural basis by which receptor and GAG interactions mediate CXCL7 function. Using solution nuclear magnetic resonance (NMR) spectroscopy, we characterized the binding of CXCL7 monomer to the CXCR2 N-terminal domain (CXCR2Nd) that constitutes a critical docking site and to GAG heparin. We found that CXCR2Nd binds a hydrophobic groove and that ionic interactions also play a role in mediating binding. Heparin binds a set of contiguous basic residues indicating a prominent role for ionic interactions. Modeling studies reveal that the binding interface is dynamic and that GAG adopts different binding geometries. Most importantly, several residues involved in GAG binding are also involved in receptor interactions, suggesting that GAG-bound monomer cannot activate the receptor. Further, this is the first study that describes the structural basis of receptor and GAG interactions of a native monomer of the neutrophil-activating chemokine family.

Original languageEnglish (US)
Article number508
JournalInternational Journal of Molecular Sciences
Volume18
Issue number3
DOIs
StatePublished - Mar 1 2017

Fingerprint

Interleukin-8B Receptors
heparins
Glycosaminoglycans
Heparin
monomers
Monomers
A73025
Chemokines
neutrophils
interactions
Neutrophil Infiltration
Dimerization
thrombosis
Platelets
Neutrophils
Thrombosis
Magnetic Resonance Spectroscopy
Blood Platelets
Dimers
Nuclear magnetic resonance spectroscopy

Keywords

  • Chemokine
  • CXCL7
  • CXCR2
  • Glycosaminoglycan
  • Heparin
  • Monomer
  • NAP-2
  • NMR

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Computer Science Applications
  • Spectroscopy
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Structural basis of native CXCL7 monomer binding to CXCR2 receptor N-domain and glycosaminoglycan heparin. / Brown, Aaron J.; Sepuru, Krishna Mohan; Rajarathnam, Krishna.

In: International Journal of Molecular Sciences, Vol. 18, No. 3, 508, 01.03.2017.

Research output: Contribution to journalArticle

@article{121596d39568406686a1491b3b5744e1,
title = "Structural basis of native CXCL7 monomer binding to CXCR2 receptor N-domain and glycosaminoglycan heparin",
abstract = "CXCL7, a chemokine highly expressed in platelets, orchestrates neutrophil recruitment during thrombosis and related pathophysiological processes by interacting with CXCR2 receptor and sulfated glycosaminoglycans (GAG). CXCL7 exists as monomers and dimers, and dimerization (~50 µM) and CXCR2 binding (~10 nM) constants indicate that CXCL7 is a potent agonist as a monomer. Currently, nothing is known regarding the structural basis by which receptor and GAG interactions mediate CXCL7 function. Using solution nuclear magnetic resonance (NMR) spectroscopy, we characterized the binding of CXCL7 monomer to the CXCR2 N-terminal domain (CXCR2Nd) that constitutes a critical docking site and to GAG heparin. We found that CXCR2Nd binds a hydrophobic groove and that ionic interactions also play a role in mediating binding. Heparin binds a set of contiguous basic residues indicating a prominent role for ionic interactions. Modeling studies reveal that the binding interface is dynamic and that GAG adopts different binding geometries. Most importantly, several residues involved in GAG binding are also involved in receptor interactions, suggesting that GAG-bound monomer cannot activate the receptor. Further, this is the first study that describes the structural basis of receptor and GAG interactions of a native monomer of the neutrophil-activating chemokine family.",
keywords = "Chemokine, CXCL7, CXCR2, Glycosaminoglycan, Heparin, Monomer, NAP-2, NMR",
author = "Brown, {Aaron J.} and Sepuru, {Krishna Mohan} and Krishna Rajarathnam",
year = "2017",
month = "3",
day = "1",
doi = "10.3390/ijms18030508",
language = "English (US)",
volume = "18",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "3",

}

TY - JOUR

T1 - Structural basis of native CXCL7 monomer binding to CXCR2 receptor N-domain and glycosaminoglycan heparin

AU - Brown, Aaron J.

AU - Sepuru, Krishna Mohan

AU - Rajarathnam, Krishna

PY - 2017/3/1

Y1 - 2017/3/1

N2 - CXCL7, a chemokine highly expressed in platelets, orchestrates neutrophil recruitment during thrombosis and related pathophysiological processes by interacting with CXCR2 receptor and sulfated glycosaminoglycans (GAG). CXCL7 exists as monomers and dimers, and dimerization (~50 µM) and CXCR2 binding (~10 nM) constants indicate that CXCL7 is a potent agonist as a monomer. Currently, nothing is known regarding the structural basis by which receptor and GAG interactions mediate CXCL7 function. Using solution nuclear magnetic resonance (NMR) spectroscopy, we characterized the binding of CXCL7 monomer to the CXCR2 N-terminal domain (CXCR2Nd) that constitutes a critical docking site and to GAG heparin. We found that CXCR2Nd binds a hydrophobic groove and that ionic interactions also play a role in mediating binding. Heparin binds a set of contiguous basic residues indicating a prominent role for ionic interactions. Modeling studies reveal that the binding interface is dynamic and that GAG adopts different binding geometries. Most importantly, several residues involved in GAG binding are also involved in receptor interactions, suggesting that GAG-bound monomer cannot activate the receptor. Further, this is the first study that describes the structural basis of receptor and GAG interactions of a native monomer of the neutrophil-activating chemokine family.

AB - CXCL7, a chemokine highly expressed in platelets, orchestrates neutrophil recruitment during thrombosis and related pathophysiological processes by interacting with CXCR2 receptor and sulfated glycosaminoglycans (GAG). CXCL7 exists as monomers and dimers, and dimerization (~50 µM) and CXCR2 binding (~10 nM) constants indicate that CXCL7 is a potent agonist as a monomer. Currently, nothing is known regarding the structural basis by which receptor and GAG interactions mediate CXCL7 function. Using solution nuclear magnetic resonance (NMR) spectroscopy, we characterized the binding of CXCL7 monomer to the CXCR2 N-terminal domain (CXCR2Nd) that constitutes a critical docking site and to GAG heparin. We found that CXCR2Nd binds a hydrophobic groove and that ionic interactions also play a role in mediating binding. Heparin binds a set of contiguous basic residues indicating a prominent role for ionic interactions. Modeling studies reveal that the binding interface is dynamic and that GAG adopts different binding geometries. Most importantly, several residues involved in GAG binding are also involved in receptor interactions, suggesting that GAG-bound monomer cannot activate the receptor. Further, this is the first study that describes the structural basis of receptor and GAG interactions of a native monomer of the neutrophil-activating chemokine family.

KW - Chemokine

KW - CXCL7

KW - CXCR2

KW - Glycosaminoglycan

KW - Heparin

KW - Monomer

KW - NAP-2

KW - NMR

UR - http://www.scopus.com/inward/record.url?scp=85014122244&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85014122244&partnerID=8YFLogxK

U2 - 10.3390/ijms18030508

DO - 10.3390/ijms18030508

M3 - Article

C2 - 28245630

AN - SCOPUS:85014122244

VL - 18

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 3

M1 - 508

ER -