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The chemokine X-factor: Structure-function analysis of the CXC motif at CXCR4 and ACKR3.
Wedemeyer, Michael J; Mahn, Sarah A; Getschman, Anthony E; Crawford, Kyler S; Peterson, Francis C; Marchese, Adriano; McCorvy, John D; Volkman, Brian F.
Afiliación
  • Wedemeyer MJ; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
  • Mahn SA; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
  • Getschman AE; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
  • Crawford KS; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
  • Peterson FC; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
  • Marchese A; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
  • McCorvy JD; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
  • Volkman BF; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. Electronic address: bvolkman@mcw.edu.
J Biol Chem ; 295(40): 13927-13939, 2020 10 02.
Article en En | MEDLINE | ID: mdl-32788219
The human chemokine family consists of 46 protein ligands that induce chemotactic cell migration by activating a family of 23 G protein-coupled receptors. The two major chemokine subfamilies, CC and CXC, bind distinct receptor subsets. A sequence motif defining these families, the X position in the CXC motif, is not predicted to make significant contacts with the receptor, but instead links structural elements associated with binding and activation. Here, we use comparative analysis of chemokine NMR structures, structural modeling, and molecular dynamic simulations that suggested the X position reorients the chemokine N terminus. Using CXCL12 as a model CXC chemokine, deletion of the X residue (Pro-10) had little to no impact on the folded chemokine structure but diminished CXCR4 agonist activity as measured by ERK phosphorylation, chemotaxis, and Gi/o-mediated cAMP inhibition. Functional impairment was attributed to over 100-fold loss of CXCR4 binding affinity. Binding to the other CXCL12 receptor, ACKR3, was diminished nearly 500-fold. Deletion of Pro-10 had little effect on CXCL12 binding to the CXCR4 N terminus, a major component of the chemokine-GPCR interface. Replacement of the X residue with the most frequent amino acid at this position (P10Q) had an intermediate effect between WT and P10del in each assay, with ACKR3 having a higher tolerance for this mutation. This work shows that the X residue helps to position the CXCL12 N terminus for optimal docking into the orthosteric pocket of CXCR4 and suggests that the CC/CXC motif contributes directly to receptor selectivity by orienting the chemokine N terminus in a subfamily-specific direction.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores CXCR4 / Quimiocina CXCL12 / Receptores CXCR / Simulación de Dinámica Molecular / Simulación del Acoplamiento Molecular Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Biol Chem Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores CXCR4 / Quimiocina CXCL12 / Receptores CXCR / Simulación de Dinámica Molecular / Simulación del Acoplamiento Molecular Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Biol Chem Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos