The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D
Love CA, Harlos K, Mavaddat N, Davis SJ, Stuart DI, Jones EY, Esnouf RM. (2003), Nat Struct Biol. 10, 843-8
Semaphorins, proteins characterized by an extracellular sema domain, regulate axon guidance, immune function and angiogenesis. The crystal structure of SEMA4D (residues 1-657) shows the sema topology to be a seven-bladed beta-propeller, revealing an unexpected homology with integrins. The sema beta-propeller contains a distinctive 77-residue insertion between beta-strands C and D of blade 5. Blade 7 is followed by a domain common to plexins, semaphorins and integrins (PSI domain), which forms a compact cysteine knot abutting the side of the propeller, and an Ig-like domain. The top face of the beta-propeller presents prominent loops characteristic of semaphorins. In addition to limited contact between the Ig-like domains, the homodimer is stabilized through extensive interactions between the top faces in a sector of the beta-propeller used for heterodimerization in integrins. This face of the propeller also mediates ligand binding in integrins, and functional data for semaphorin-receptor interactions map to the equivalent surface.
Key figure: Functional information mapped to the sSEMA4D structure
A stereo Cα trace of the homodimer. Mutations and residues implicated in cancer biology are mapped to the equivalent SEMA4D Cα atoms, shown as spheres and, for one subunit, color coded as in Figure 2a. Cancer-related mutations or polymorphisms (yellow), from top to bottom, map to residues 368, 313, 386, 437, 524 and 528, respectively. Residues whose mutation abolishes function (cyan) map to residues 502, 501, 496 and 495, from left to right, respectively. In the same subunit the propeller domain is blue; the extrusion (at top), the PSI and the Ig-like domains are magenta, pink and coral, respectively. In the second subunit the 70 amino acids implicated in specificity are green. A peptide mimetic of the integrin-binding Arg-Gly-Asp motif from a complex with the crystal structure of αVβ3 is shown, appropriately superposed, in red. An Ig-like domain from a neighboring molecule in the sSEMA4D crystal lattice is black.