Crystal structure of a C-terminal fragment of growth arrest-specific protein Gas6. Receptor tyrosine kinase activation by laminin G-like domains.
Receptor tyrosine kinases of the Axl family are activated by Gas6, the product of growth arrest-specific gene 6. Gas6-Axl signaling is implicated in cell survival, adhesion, and migration. The receptor-binding site of Gas6 is located within a C-terminal pair of laminin G-like (LG) domains that do not resemble any other receptor tyrosine kinase ligand. We report the crystal structure at 2.2-A resolution of a Gas6 fragment spanning both LG domains (Gas6-LG). The structure reveals a V-shaped arrangement of LG domains strengthened by an interdomain calcium-binding site. LG2 of Gas6-LG contains two unusual features: an alpha-helix cradled by one edge of the LG beta-sandwich and a conspicuous patch of surface-exposed hydrophobic residues. Mutagenesis of some residues in this patch reduces Gas6-LG binding to the extracellular domain of Axl as well as Axl activation in glioblastoma cells, identifying a component of the receptor-binding site of Gas6.
Sasaki
Takako
T
Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany.
Knyazev
Pjotr G
PG
Cheburkin
Yuri
Y
Göhring
Walter
W
Tisi
Dominic
D
Ullrich
Axel
A
Timpl
Rupert
R
Hohenester
Erhard
E
D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D018360:Crystallography, X-Ray; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured; D000099255:Growth Arrest-Specific Protein 6
D002118:Calcium; D016895:Culture Media, Serum-Free; D018076:DNA, Complementary; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D008024:Ligands; D011506:Proteins; D000099255:Growth Arrest-Specific Protein 6