title: Structural and agonist properties of XCL2, the other member of the C-chemokine subfamily.
abstract: Known for its unusual metamorphic native state structure, XCL1 has been the focus of most efforts to elucidate the structural, functional, and physiological properties of chemokines in the C subfamily. By comparison, its closely related paralog XCL2 remains virtually uncharacterized. Based on the importance of the chemokine N-terminus in receptor activation, it was hypothesized that two amino acid differences in XCL2 would alter its agonist activity relative to XCL1 for their shared receptor XCR1. This present study reveals several properties of XCL2 that were unexamined until now. Structurally, XCL1 and XCL2 are very similar, exchanging between the monomeric chemokine fold and an unrelated dimeric state under physiological NaCl and temperature conditions. Ca(2+) flux, chemotaxis, and heparin binding assays showed that the monomer form of XCL2 is responsible for G protein-coupled receptor activation while the dimeric form is important for GAG binding. Despite their high structural similarity, XCL2 displays a slightly higher affinity for heparin than XCL1. Because their in vitro functional profiles are virtually identical, distinct physiological roles for XCL1 and XCL2 are probably encoded at the level of expression.
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Fox
authors.affiliation: Division of Chemotherapy, Kinki University, Faculty of Pharmacy, Higashi-osaka 577-8502, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Tyler
authors.affiliation: Department of Pediatric Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Sander
authors.affiliation: Kinki University, Faculty of Medicine, Osaka-Sayama, Osaka 589-851, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshie
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: bvolkman@mcw.edu.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Volkman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D019744:Chemokines, C / Q000737:chemistry*; D002633:Chemotaxis; D019295:Computational Biology; D006493:Heparin / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008222:Lymphokines / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011485:Protein Binding; D011489:Protein Denaturation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012795:Sialoglycoproteins / Q000378:metabolism; D015398:Signal Transduction; D012965:Sodium Chloride / Q000737:chemistry; D013696:Temperature; D013816:Thermodynamics; D014508:Urea / Q000737:chemistry
chemical_list: D019744:Chemokines, C; D008222:Lymphokines; D012795:Sialoglycoproteins; C092390:XCL1 protein, human; C490470:XCL2 protein, human; C018997:lymphotactin; D012965:Sodium Chloride; D014508:Urea; D006493:Heparin; D002118:Calcium
keywords: Ca(2+) flux; Chemotaxis; Lymphotactin; XCL1; XCL2