THE CRYSTAL-STRUCTURE OF AMYLOIDOGENIC LEU(55) -] PRO TRANSTHYRETIN VARIANT REVEALS A POSSIBLE PATHWAY FOR TRANSTHYRETIN POLYMERIZATION INTO AMYLOID FIBRILS

The x-ray crystal structure of the amyloidogenic Leu(55) --> Pro trans thyretin (TTR) variant, implicated as the causative agent in early-ons et familial amyloidotic polyneuropathy (Jacobson, D. R., McFarlin, D. E., Kane, I., and Buxbaum, J. N. (1992) Hum. Genet. 89, 353-356), has been solved by molecular replacement, refined at 2.7 Angstrom to a R-c ryst value of 0.190 (F-obs > 2.0 sigma), and compared with wild-type t ransthyretin to understand the molecular mechanism(s) involved in amyl oidogenesis. Leu(55) --> Pro TTR crystallizes in space group C2, with eight monomers in the asymmetric unit, and the observed packing contac ts are considerably different from those described for the wild-type p rotein. Refinement of the crystal structure shows that the proline for leucine substitution disrupts the hydrogen bonds between strands D an d A, resulting in different interface contacts. Based on the assumptio n that the observed packing contacts may be significant for amyloidoge nesis, a model for the TTR amyloid is proposed. It consists of a tubul ar structure with inner and outer diameters approximately of 30 and 10 0 Angstrom and four monomers per cross-section.