Functional characterization of the C—C chemokine-like molecules encoded by molluscum contagiosum virus types 1 and 2

Krathwohl, Mitchell D.; Hromas, Robert; Brown, Darron R.; Broxmeyer, Hal E.; Fife, Kenneth H.

doi:10.1073/pnas.94.18.9875

Cited by 78 publications

(45 citation statements)

References 31 publications

(32 reference statements)

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“…We have also shown that [1ϩ9 -76]MCP-1 functions as an antagonist via competitive inhibition of the WT protein. This suggests that virally encoded receptor antagonists that have natural N-terminal deletions, such as MC148R (60), may function in a similar manner. We believe these results provide new molecular details and insight into the mechanism of leukocyte chemotaxis.…”

Section: Disulfide Cross-linked Wt*(c77) and [1ϩ9 -76](c77) Bind And mentioning

confidence: 99%

“…An exception to this is MCP-3, which possesses a serine at the corresponding position and is monomeric (59). The viral CC chemokines, MC148R1 and MC148R2 (60), are also missing this proline, which may point to a function of oligomerization that is required for certain host chemokines but not for these viral chemokines.…”

Section: Disulfide Cross-linked Wt*(c77) and [1ϩ9 -76](c77) Bind And mentioning

confidence: 99%

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Monomeric Monocyte Chemoattractant Protein-1 (MCP-1) Binds and Activates the MCP-1 Receptor CCR2B

Paavola¹,

Hemmerich²,

Grünberger³

et al. 1998

Journal of Biological Chemistry

182

223

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To address the role of dimerization in the function of the monocyte chemoattractant protein-1, MCP-1, we mutated residues that comprise the core of the dimerization interface and characterized the ability of these mutants to dimerize and to bind and activate the MCP-1 receptor, CCR2b. One mutant, P8A*, does not dimerize. However, it has wild type binding affinity, stimulates chemotaxis, inhibits adenylate cyclase, and stimulates calcium influx with wild type potency and efficacy. These data suggest that MCP-1 binds and activates its receptor as a monomer. In contrast, Y13A*, another monomeric mutant, has a 100-fold weaker binding affinity, is a much less potent inhibitor of adenylate cyclase and stimulator of calcium influx, and is unable to stimulate chemotaxis. Thus Tyr 13 may make important contacts with the receptor that are required for high affinity binding and signal transduction. We also explored whether a mutant, Chemokines are small secreted proteins that function as intercellular messengers to control migration and activation of specific subsets of leukocytes (1-3). This process is mediated by the interaction of chemokines with seven transmembrane Gprotein-coupled receptors on the surface of target cells. Interest in these proteins was first stimulated by the observation of elevated levels in a number of inflammatory diseases (4, 5) including rheumatoid arthritis (6, 7), arteriosclerosis (8, 9), and asthma (10). Although it is not clear whether excessive production is the cause or consequence of these diseases, the demonstration that neutralizing antibodies (11-13) reduced symptoms in a number of animal models generated optimism that receptor antagonists may have therapeutic benefit (14). Recently, it has been shown that certain chemokine receptors also serve as obligate coreceptors for entry of the human immunodeficiency virus into CD4ϩ cells (15)(16)(17) and that viral replication can be inhibited by the ligands of the coreceptors (18 -21). Thus a wide range of clinically important diseases are associated with chemokines and their receptors, motivating many studies to understand the molecular details of chemokine function.Chemokines have been classified into two major families based on their pattern of cysteine residues, their chromosomal location, and their cell specificities (22). ␣-Chemokines such as IL-8 1 have a conserved CXC cysteine motif and act predominantly on neutrophils, whereas ␤-chemokines have a CC signature and attract monocytes and T-cells. The recently discovered chemokines lymphotactin (23) and fractalkine/neurotactin (24,25) are characterized by C and CX 3 C motifs, respectively, and chemoattract T-cells and NK cells. Mutagenesis studies, particularly of ␣-and ␤-chemokines, have provided some insight into the structural determinants of receptor binding and the specificity of these proteins, but many details have yet to emerge.Considerable effort has been devoted to characterizing the stochiometry of chemokine-receptor complexes because most chemokines oligomerize to an extent tha...

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Section: Disulfide Cross-linked Wt*(c77) and [1ϩ9 -76](c77) Bind And mentioning

confidence: 99%

Section: Disulfide Cross-linked Wt*(c77) and [1ϩ9 -76](c77) Bind And mentioning

confidence: 99%

Monomeric Monocyte Chemoattractant Protein-1 (MCP-1) Binds and Activates the MCP-1 Receptor CCR2B

Paavola¹,

Hemmerich²,

Grünberger³

et al. 1998

Journal of Biological Chemistry

182

223

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“…It has been postulated that these chemokine homologues act as dominant negative inhibitors of normal chemokine function, blocking the recruitment of leukocytes to a viral infection. For example, we described the presence of two homologues of Mip-1α in the genome of Molluscum Contagiosum [52]. These chemokines inhibited the action of normal human Mip-1α.…”

Section: Chemokines and Diseasementioning

confidence: 99%

Chemokine Regulation of Normal and Pathologic Immune Responses

2001

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Chemokines are small basic proteins that are the major mediators of all leukocyte migration. There are at least 46 distinct chemokines, and 19 chemokine receptors, making it easily the largest cytokine family. Chemokines can be both beneficial and harmful, by either stimulating an appropriate immune response to microbial invasion, or by mediating pathologic tissue destruction in many types of human disease. Chemokines have been implicated in the tissue destruction seen in autoimmune diseases, atherosclerosis, allograft rejection, and neoplasia. Chemokines also play essential roles in normal lymphocyte trafficking to primary and secondary lymphoid organs for antigen presentation and lymphocyte maturation. Chemokines also regulate hematopoietic stem and progenitor cell homing and proliferation. Therefore, it is likely that chemokines will become important targets for pharmacologic intervention in a wide variety of human diseases in the future.

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“…It appears that multiple chemokines interact and direct the migration of lymphocytes in a given tissue microenvironment. It has been reported that some viral chemokines (vMIP-II of Kaposi's sarcoma-associated herpesvirus; a molluscum contagiosum virus type I chemokine) inhibited the chemotactic activity of the host's chemokines [104,105], suggesting a possible mechanism to avoid the host immune system.…”

Section: Trafficking Of Lymphocytes In Disease Modelsmentioning

confidence: 99%

Chemokines: signal lamps for trafficking of T and B cells for development and effector function

Kim

Broxmeyer

1999

Journal of Leukocyte Biology

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328

251

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Functional characterization of the C—C chemokine-like molecules encoded by molluscum contagiosum virus types 1 and 2

Cited by 78 publications

References 31 publications

Monomeric Monocyte Chemoattractant Protein-1 (MCP-1) Binds and Activates the MCP-1 Receptor CCR2B

Monomeric Monocyte Chemoattractant Protein-1 (MCP-1) Binds and Activates the MCP-1 Receptor CCR2B

Chemokine Regulation of Normal and Pathologic Immune Responses

Chemokines: signal lamps for trafficking of T and B cells for development and effector function

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