PMID- 9837883
OWN - NLM
STAT- MEDLINE
DCOM- 19990114
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 273
IP  - 50
DP  - 1998 Dec 11
TI  - Monomeric monocyte chemoattractant protein-1 (MCP-1) binds and activates the 
      MCP-1 receptor CCR2B.
PG  - 33157-65
AB  - 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 Tyr13 may make important contacts with the receptor that are required for 
      high affinity binding and signal transduction. We also explored whether a mutant, 
      [1+9-76]MCP-1 (MCP-1 lacking residues 2-8), antagonizes wild type MCP-1 by 
      competitive inhibition, or by a dominant negative mechanism wherein heterodimers 
      of MCP-1 and [1+9-76]MCP-1 bind to the receptor but are signaling incompetent. 
      Consistent with the finding that MCP-1 can bind and activate the receptor as a 
      monomer, we demonstrate that binding of MCP-1 in the presence of [1+9-76]MCP-1 
      over a range of concentrations of both ligands fits well to a simple model in 
      which monomeric [1+9-76]MCP-1 functions as a competitive inhibitor of monomeric 
      MCP-1. These results are crucial for elucidating the molecular details of 
      receptor binding and activation, for interpreting mutagenesis data, for 
      understanding how antagonistic chemokine variants function, and for the design of 
      receptor antagonists.
FAU - Paavola, C D
AU  - Paavola CD
AD  - Department of Molecular and Cell Biology, University of California at Berkeley, 
      Berkeley, California 94720, USA.
FAU - Hemmerich, S
AU  - Hemmerich S
FAU - Grunberger, D
AU  - Grunberger D
FAU - Polsky, I
AU  - Polsky I
FAU - Bloom, A
AU  - Bloom A
FAU - Freedman, R
AU  - Freedman R
FAU - Mulkins, M
AU  - Mulkins M
FAU - Bhakta, S
AU  - Bhakta S
FAU - McCarley, D
AU  - McCarley D
FAU - Wiesent, L
AU  - Wiesent L
FAU - Wong, B
AU  - Wong B
FAU - Jarnagin, K
AU  - Jarnagin K
FAU - Handel, T M
AU  - Handel TM
LA  - eng
GR  - R01 AI037113/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (CCR2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Disulfides)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Receptors, Chemokine)
RN  - 0 (Receptors, Cytokine)
RN  - 0 (Recombinant Proteins)
SB  - IM
MH  - Chemokine CCL2/*metabolism
MH  - Dimerization
MH  - Disulfides/chemistry
MH  - Humans
MH  - Magnetic Resonance Spectroscopy
MH  - Protein Binding
MH  - Receptors, CCR2
MH  - *Receptors, Chemokine
MH  - Receptors, Cytokine/antagonists & inhibitors/*metabolism
MH  - Recombinant Proteins/metabolism
EDAT- 1998/12/05 00:00
MHDA- 1998/12/05 00:01
CRDT- 1998/12/05 00:00
PHST- 1998/12/05 00:00 [pubmed]
PHST- 1998/12/05 00:01 [medline]
PHST- 1998/12/05 00:00 [entrez]
AID - S0021-9258(19)88515-0 [pii]
AID - 10.1074/jbc.273.50.33157 [doi]
PST - ppublish
SO  - J Biol Chem. 1998 Dec 11;273(50):33157-65. doi: 10.1074/jbc.273.50.33157.