Solution structure of CXCL5--a novel chemokine and adipokine implicated in inflammation and obesity.
The chemokine CXCL5 is selectively expressed in highly specialized cells such as epithelial type II cells in the lung and white adipose tissue macrophages in muscle, where it mediates diverse functions from combating microbial infections by regulating neutrophil trafficking to promoting obesity by inhibiting insulin signaling. Currently very little is known regarding the structural basis of how CXCL5 mediates its novel functions. Towards this missing knowledge, we have solved the solution structure of the CXCL5 dimer by NMR spectroscopy. CXCL5 is a member of a subset of seven CXCR2-activating chemokines (CAC) that are characterized by the highly conserved ELR motif in the N-terminal tail. The structure shows that CXCL5 adopts the typical chemokine fold, but also reveals several distinct differences in the 30 s loop and N-terminal residues; not surprisingly, crosstalk between N-terminal and 30 s loop residues have been implicated as a major determinant of receptor activity. CAC function also involves binding to highly sulfated glycosaminoglycans (GAG), and the CXCL5 structure reveals a distinct distribution of positively charged residues, suggesting that differences in GAG interactions also influence function. The availability of the structure should now facilitate the design of experiments to better understand the molecular basis of various CXCL5 functions, and also serve as a template for the design of inhibitors for use in a clinical setting.
Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Krishna Mohan
KM
Sepuru
Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Krishna Mohan
KM
Poluri
Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas, United States of America.
Krishna
K
Rajarathnam
D054392:Adipokines / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D054365:Chemokine CXCL5 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D009765:Obesity; D017510:Protein Folding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary
D054392:Adipokines; C486263:CXCL5 protein, human; D054365:Chemokine CXCL5