title: Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12.
abstract: Stem cell homing and breast cancer metastasis are orchestrated by the chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4. Here, we report the nuclear magnetic resonance structure of a constitutively dimeric SDF-1 in complex with a CXCR4 fragment that contains three sulfotyrosine residues important for a high-affinity ligand-receptor interaction. CXCR4 bridged the SDF-1 dimer interface so that sulfotyrosines sTyr7 and sTyr12 of CXCR4 occupied positively charged clefts on opposing chemokine subunits. Dimeric SDF-1 induced intracellular Ca2+ mobilization but had no chemotactic activity; instead, it prevented native SDF-1-induced chemotaxis, suggesting that it acted as a potent partial agonist. Our work elucidates the structural basis for sulfotyrosine recognition in the chemokine-receptor interaction and suggests a strategy for CXCR4-targeted drug development.
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Veldkamp
authors.forename: Christoph
authors.initials: C
authors.lastname: Seibert
authors.forename: Francis C
authors.initials: FC
authors.lastname: Peterson
authors.forename: Norberto B
authors.initials: NB
authors.lastname: De la Cruz
authors.forename: John C
authors.initials: JC
authors.lastname: Haugner
authors.forename: Harihar
authors.initials: H
authors.lastname: Basnet
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sakmar
authors.forename: Brian F
authors.initials: BF
authors.lastname: Volkman
mesh_terms: D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000737:chemistry* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D019718:Receptors, CXCR4 / Q000737:chemistry* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; C005662:tyrosine O-sulfate; D014443:Tyrosine; D002118:Calcium
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