HINGE BENDING WITHIN THE CYTOKINE RECEPTOR SUPERFAMILY REVEALED BY THE 2.4 ANGSTROM CRYSTAL-STRUCTURE OF THE EXTRACELLULAR DOMAIN OF RABBIT-TISSUE FACTOR

Tissue factor (TF), a member of the cytokine receptor superfamily, is the obligate cofactor of coagulation factor VIIa (FVIIa), and has a pi votal role in initiating the extrinsic pathway of blood coagulation th rough formation of the TF FVIIa complex. The crystal structure of the extracellular portion of rabbit TF has been solved at 2.35 Angstrom re solution and refined to a crystallographic R-value of 19.1% (free R-va lue, 27.7%). Like the human homologue, the extracellular portion consi sts of two fibronectin type III domains connected by a short alpha-hel ical segment. Unexpectedly, the two molecules in the crystallographic asymmetric unit differ in their relative domain-domain orientation, re vealing unsuspected hinge motion consisting of a rotation of about 12. 7 degrees around an axis intersecting the linker segment at residue 10 6. Superposition of rabbit tissue factor with free and bound human tis sue factor allows for the detection of an identical, albeit smaller, h inge motion in human TF induced upon binding of FVIIa. This raises the possibility that a very similar hinge axis may be present in other me mbers of the cytokine receptor superfamily.