The Structure of the RAGE:S100A6 Complex Reveals a Unique Mode of Homodimerization for S100 Proteins.
S100 proteins are calcium-dependent regulators of homeostatic processes. Upon cellular response to stress, and notably during tumorigenesis, they relocalize to the extracellular environment where they induce pro-inflammatory signals by activating the receptor for advanced glycation end products (RAGE), thereby facilitating tumor growth and metastasis. Despite its importance in sustaining inflammation, the structural basis for RAGE-S100 crosstalk is still unknown. Here we report two crystal structures of the RAGE:S100A6 complex encompassing a full-length RAGE ectodomain. The structures, in combination with a comprehensive interaction analysis, suggest that the primary S100A6 binding site is formed by the RAGE C1 domain. Complex formation with S100A6 induces a unique dimeric conformation of RAGE that appears suited for signal transduction and intracellular effector recruitment. Intriguingly, S100A6 adopts a dimeric conformation radically different from all known S100 dimers. We discuss the physiological relevance of this non-canonical homodimeric form in vivo.
Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus, Denmark. Electronic address: laure.yatime@inserm.fr.
Laure
L
Yatime
Department of Biomedicine, Danish Research Institute of Translational Neuroscience - DANDRITE, Aarhus University, Ole Worms Allé 1170, 8000 Aarhus, Denmark.
Cristine
C
Betzer
Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus, Denmark.
Rasmus Kjeldsen
RK
Jensen
Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus, Denmark.
Sofia
S
Mortensen
Department of Biomedicine, Danish Research Institute of Translational Neuroscience - DANDRITE, Aarhus University, Ole Worms Allé 1170, 8000 Aarhus, Denmark.
Poul Henning
PH
Jensen
Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus, Denmark. Electronic address: gra@mbg.au.dk.
Gregers Rom
GR
Andersen
D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D000067759:Receptor for Advanced Glycation End Products / Q000737:chemistry* / Q000378:metabolism*; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
C000593871:AGER protein, human; D018797:Cell Cycle Proteins; D000067759:Receptor for Advanced Glycation End Products; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins; C055351:S100A6 protein, human
RAGE; S100 proteins; pattern recognition receptor; signaling complex; stress response