Chemokine signaling specificity: essential role for the N-terminal domain of chemokine receptors.
Chemokine IL-8 (CXCL8) binds to its cognate receptors CXCR1 and CXCR2 to induce inflammatory responses, wound healing, tumorogenesis, and neuronal survival. Here we identify the N-loop residues in IL-8 (H18 and F21) and the receptor N-termini as the major structural determinants regulating the rate of receptor internalization, which in turn controlled the activation profile of ERK1/2, a central component of the receptor/ERK signaling pathway that dictates signal specificity. Our data further support the idea that the chemokine receptor core acts as a plastic scaffold. Thus, the diversity and intensity of inflammatory and noninflammatory responses mediated by chemokine receptors appear to be primarily determined by the initial interaction between the receptor N-terminus and the N-loop of chemokines.
Prado
Gregory N
GN
Department of Neuroscience and Cell Biology, Sealy Centers for Molecular Medicine and Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Suetomi
Katsutoshi
K
Shumate
David
D
Maxwell
Carrie
C
Ravindran
Aishwarya
A
Rajarathnam
Krishna
K
Navarro
Javier
J
D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D054360:Chemokine CXCL1; D054427:Chemokine CXCL6; D019743:Chemokines, CXC / Q000378:metabolism; D002522:Chlorocebus aethiops; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D050506:Mutant Chimeric Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits; D053700:Receptors, Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
C475829:CXCL1 protein, human; C515503:CXCL6 protein, human; D054360:Chemokine CXCL1; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; D016209:Interleukin-8; D050506:Mutant Chimeric Proteins; D053700:Receptors, Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3