Extended Data Fig. 5: Structure of ALKAL1 and ALKAL2.
From: Structural basis of cytokine-mediated activation of ALK family receptors
a, Structural superposition of the conserved C-terminal segments of ALKAL1 and ALKAL2 (coloured in an N- (blue) to C-terminus (red) gradient) as observed in their complexes with cognate receptors. ALKAL1 and ALKAL2 share high sequence identity (66%) in their C-terminal domain, but have variable N-terminal regions. ALKAL1 residues in the interface between helix A and helices B and C are shown as sticks. αA connects via a conserved short loop to a helical hairpin constructed from αB and αC, which in turn are tethered by two conserved disulfides. A conserved stretch of ~10 residues preceding αA was not ordered in the reported structures, suggesting they might help to stabilize the soluble forms of these cytokines rather than contribute to direct receptor engagement or might help reduce the entropic cost of binding. b, Surface representation of ALKAL1 coloured according to the Eisenberg hydrophobicity scale. Hydroxyl groups surrounding the central cavity are shown as red spheres. c, Sequence alignment by ClustalOmega of human ALKAL1 with ALKAL2. Residues in the interface between helix A and helices B and C are coloured according to their position. Cysteines are coloured yellow and disulfide bonds are shown as yellow lines. d, Surface representation of the LTKTG—ALKAL1 complex with LTK in ALKAL1 coloured according to the Eisenberg hydrophobicity scale (white is more hydrophobic). The black circle denotes the ALKAL1 hydrophobic cavity. e, Multiple sequence alignments of various vertebrate ALKAL1 and ALKAL2 sequences using the ESPripT server (http://espript.ibcp.fr/ESPript/ESPript/) and structural annotation according to secondary structure elements. Symbols indicate residues participating in interaction sites 1 and 2 according to the graphical legend. Hs (Homo sapiens), Mm (Mus musculus), Gg (Gallus gallus) Xl (Xenopus laevis), Xt (Xenopus tropicalis) Dr (Danio rerio). f, ALKAL1 shown in green transparent surface and ribbon representation. Residues differing with ALKAL2 are colored vermillion and labeled with the ALKAL1/ALKAL2 numbering.
