Receptor tyrosine kinases of the Axl family are activated by the vitamin K-dependent protein Gas6
Axl signalling plays important roles in cancer, spermatogenesis, immunity, and platelet function
The crystal structure at 3 .3 A resolution of a minimal human Gas6 / Axl complex reveals an assembly of 2:2 stoichiometry, in which the two immunoglobulin-like domains of the Axl ectodomain are crosslinked by the first laminin G-like domain of Gas6 , with no direct Axl / Axl or Gas6 / Gas6 contacts
There are two distinct Gas6 / Axl contacts of very different size, both featuring interactions between edge beta-strands
Structure-based mutagenesis, protein binding assays and receptor activation experiments demonstrate that both the major and minor Gas6 binding sites are required for productive transmembrane signalling
Gas6-mediated Axl dimerisation is likely to occur in two steps, with a high-affinity 1:1 Gas6 / Axl complex forming first
Only the minor Gas6 binding site is highly conserved in the other Axl family receptors , Sky / Tyro3 and Mer
Specificity at the major contact is suggested to result from the segregation of charged and apolar residues to opposite faces of the newly formed beta-sheet