CC and CX3C chemokines differentially interact with the N terminus of the human cytomegalovirus-encoded US28 receptor

Paola Casarosa; Maria Waldhoer; Patricia J LiWang; Henry F Vischer; Thomas Kledal; Henk Timmerman; Thue W Schwartz; Martine J Smit; Rob Leurs

doi:10.1074/jbc.M407536200

CC and CX3C chemokines differentially interact with the N terminus of the human cytomegalovirus-encoded US28 receptor

Paola Casarosa, Maria Waldhoer, Patricia J LiWang, Henry F Vischer, Thomas Kledal, Henk Timmerman, Thue W Schwartz, Martine J Smit, Rob Leurs

Department of Neuroscience

55 Citations (Scopus)

Abstract

Human cytomegalovirus (HCMV) is the causative agent of life-threatening systemic diseases in immunocompromised patients as well as a risk factor for vascular pathologies, like atherosclerosis, in immunocompetent individuals. HCMV encodes a G-protein-coupled receptor (GPCR), referred to as US28, that displays homology to the human chemokine receptor CCR1 and binds several chemokines of the CC family as well as the CX3C chemokine fractalkine with high affinity. Most importantly, following HCMV infection, US28 activates several intracellular pathways, either constitutively or in a chemokine-dependent manner. In this study, our goal was to understand the molecular interactions between chemokines and the HCMV-encoded US28 receptor. To achieve this goal, a double approach has been used, consisting in the analysis of both receptor and ligand mutants. This approach has led us to identify several amino acids located in the N terminus of US28 that differentially contribute to the high affinity binding of CC versus CX3C chemokines. Additionally, our results highlight the importance of secondary modifications occurring at US28, such as sulfation, for ligand recognition. Finally, the effects of chemokine dimerization and interaction with glycosaminoglycans (GAGs) on chemokine binding and activation of US28 were investigated as well using CCL4 as model ligand. In line with the two-state model describing chemokine/receptor interaction, we show that an aromatic residue in the N-loop region of CCL4 promotes tight binding to US28, whereas receptor activation depends on the presence of the N terminus of CCL4, as shown previously for CCR5.

Original language	English
Journal	Journal of Biological Chemistry
Volume	280
Issue number	5
Pages (from-to)	3275-3285
Number of pages	10
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.M407536200
Publication status	Published - 2005

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@article{0a05eec074c211dbbee902004c4f4f50,

title = "CC and CX3C chemokines differentially interact with the N terminus of the human cytomegalovirus-encoded US28 receptor",

abstract = "Human cytomegalovirus (HCMV) is the causative agent of life-threatening systemic diseases in immunocompromised patients as well as a risk factor for vascular pathologies, like atherosclerosis, in immunocompetent individuals. HCMV encodes a G-protein-coupled receptor (GPCR), referred to as US28, that displays homology to the human chemokine receptor CCR1 and binds several chemokines of the CC family as well as the CX3C chemokine fractalkine with high affinity. Most importantly, following HCMV infection, US28 activates several intracellular pathways, either constitutively or in a chemokine-dependent manner. In this study, our goal was to understand the molecular interactions between chemokines and the HCMV-encoded US28 receptor. To achieve this goal, a double approach has been used, consisting in the analysis of both receptor and ligand mutants. This approach has led us to identify several amino acids located in the N terminus of US28 that differentially contribute to the high affinity binding of CC versus CX3C chemokines. Additionally, our results highlight the importance of secondary modifications occurring at US28, such as sulfation, for ligand recognition. Finally, the effects of chemokine dimerization and interaction with glycosaminoglycans (GAGs) on chemokine binding and activation of US28 were investigated as well using CCL4 as model ligand. In line with the two-state model describing chemokine/receptor interaction, we show that an aromatic residue in the N-loop region of CCL4 promotes tight binding to US28, whereas receptor activation depends on the presence of the N terminus of CCL4, as shown previously for CCR5.",

author = "Paola Casarosa and Maria Waldhoer and LiWang, {Patricia J} and Vischer, {Henry F} and Thomas Kledal and Henk Timmerman and Schwartz, {Thue W} and Smit, {Martine J} and Rob Leurs",

note = "Keywords: Amino Acid Sequence; Amino Acids, Aromatic; Animals; COS Cells; Cercopithecus aethiops; Chemokine CCL4; Chemokines, CC; Chemokines, CX3C; Conserved Sequence; Gene Expression; Humans; Macrophage Inflammatory Proteins; Molecular Sequence Data; Mutagenesis; Protein Binding; Protein Structure, Tertiary; Proteins; Receptors, Chemokine; Sulfur; Tyrosine; Viral Proteins",

year = "2005",

doi = "10.1074/jbc.M407536200",

language = "English",

volume = "280",

pages = "3275--3285",

journal = "Journal of Biological Chemistry",

issn = "0021-9258",

publisher = "American Society for Biochemistry and Molecular Biology, Inc.",

number = "5",

}

TY - JOUR

T1 - CC and CX3C chemokines differentially interact with the N terminus of the human cytomegalovirus-encoded US28 receptor

AU - Casarosa, Paola

AU - Waldhoer, Maria

AU - LiWang, Patricia J

AU - Vischer, Henry F

AU - Kledal, Thomas

AU - Timmerman, Henk

AU - Schwartz, Thue W

AU - Smit, Martine J

AU - Leurs, Rob

N1 - Keywords: Amino Acid Sequence; Amino Acids, Aromatic; Animals; COS Cells; Cercopithecus aethiops; Chemokine CCL4; Chemokines, CC; Chemokines, CX3C; Conserved Sequence; Gene Expression; Humans; Macrophage Inflammatory Proteins; Molecular Sequence Data; Mutagenesis; Protein Binding; Protein Structure, Tertiary; Proteins; Receptors, Chemokine; Sulfur; Tyrosine; Viral Proteins

PY - 2005

Y1 - 2005

N2 - Human cytomegalovirus (HCMV) is the causative agent of life-threatening systemic diseases in immunocompromised patients as well as a risk factor for vascular pathologies, like atherosclerosis, in immunocompetent individuals. HCMV encodes a G-protein-coupled receptor (GPCR), referred to as US28, that displays homology to the human chemokine receptor CCR1 and binds several chemokines of the CC family as well as the CX3C chemokine fractalkine with high affinity. Most importantly, following HCMV infection, US28 activates several intracellular pathways, either constitutively or in a chemokine-dependent manner. In this study, our goal was to understand the molecular interactions between chemokines and the HCMV-encoded US28 receptor. To achieve this goal, a double approach has been used, consisting in the analysis of both receptor and ligand mutants. This approach has led us to identify several amino acids located in the N terminus of US28 that differentially contribute to the high affinity binding of CC versus CX3C chemokines. Additionally, our results highlight the importance of secondary modifications occurring at US28, such as sulfation, for ligand recognition. Finally, the effects of chemokine dimerization and interaction with glycosaminoglycans (GAGs) on chemokine binding and activation of US28 were investigated as well using CCL4 as model ligand. In line with the two-state model describing chemokine/receptor interaction, we show that an aromatic residue in the N-loop region of CCL4 promotes tight binding to US28, whereas receptor activation depends on the presence of the N terminus of CCL4, as shown previously for CCR5.

AB - Human cytomegalovirus (HCMV) is the causative agent of life-threatening systemic diseases in immunocompromised patients as well as a risk factor for vascular pathologies, like atherosclerosis, in immunocompetent individuals. HCMV encodes a G-protein-coupled receptor (GPCR), referred to as US28, that displays homology to the human chemokine receptor CCR1 and binds several chemokines of the CC family as well as the CX3C chemokine fractalkine with high affinity. Most importantly, following HCMV infection, US28 activates several intracellular pathways, either constitutively or in a chemokine-dependent manner. In this study, our goal was to understand the molecular interactions between chemokines and the HCMV-encoded US28 receptor. To achieve this goal, a double approach has been used, consisting in the analysis of both receptor and ligand mutants. This approach has led us to identify several amino acids located in the N terminus of US28 that differentially contribute to the high affinity binding of CC versus CX3C chemokines. Additionally, our results highlight the importance of secondary modifications occurring at US28, such as sulfation, for ligand recognition. Finally, the effects of chemokine dimerization and interaction with glycosaminoglycans (GAGs) on chemokine binding and activation of US28 were investigated as well using CCL4 as model ligand. In line with the two-state model describing chemokine/receptor interaction, we show that an aromatic residue in the N-loop region of CCL4 promotes tight binding to US28, whereas receptor activation depends on the presence of the N terminus of CCL4, as shown previously for CCR5.

U2 - 10.1074/jbc.M407536200

DO - 10.1074/jbc.M407536200

M3 - Journal article

C2 - 15546882

SN - 0021-9258

VL - 280

SP - 3275

EP - 3285

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 5

ER -

CC and CX3C chemokines differentially interact with the N terminus of the human cytomegalovirus-encoded US28 receptor

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