A Requirement for Metamorphic Interconversion in the Antimicrobial Activity of Chemokine XCL1.
Chemokines make up a superfamily of ∼50 small secreted proteins (8-12 kDa) involved in a host of physiological processes and disease states, with several previously shown to have direct antimicrobial activity comparable to that of defensins in efficacy. XCL1 is a unique metamorphic protein that interconverts between the canonical chemokine fold and a novel all-β-sheet dimer. Phylogenetic analysis suggests that, within the chemokine family, XCL1 is most closely related to CCL20, which exhibits antibacterial activity. The in vitro antimicrobial activity of WT-XCL1 and structural variants was quantified using a radial diffusion assay (RDA) and in solution bactericidal assays against Gram-positive and Gram-negative species of bacteria. Comparisons of WT-XCL1 with variants that limit metamorphic interconversion showed a loss of antimicrobial activity when restricted to the conserved chemokine fold. These results suggest that metamorphic folding of XCL1 is required for potent antimicrobial activity.
Department of Biochemistry, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States.
Amanda M
AM
Nevins
Department of Pathology and Laboratory Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, California 90089, United States.
Akshay
A
Subramanian
Department of Pathology and Laboratory Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, California 90089, United States.
Jazma L
JL
Tapia
Department of Pathology and Laboratory Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, California 90089, United States.
David P
DP
Delgado
Department of Biochemistry, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States.
Robert C
RC
Tyler
Department of Biochemistry, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States.
Davin R
DR
Jensen
Department of Pathology and Laboratory Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, California 90089, United States.
André J
AJ
Ouellette
Department of Biochemistry, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States.
Brian F
BF
Volkman
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D019744:Chemokines, C / Q000494:pharmacology*; D006801:Humans; D010802:Phylogeny; D011485:Protein Binding; D017510:Protein Folding; D017386:Sequence Homology, Amino Acid
D000900:Anti-Bacterial Agents; D019744:Chemokines, C; C092390:XCL1 protein, human