A three-dimensional reconstruction of alpha(2)-macroglobulin for (alpha(2)M) was computed from stain images. The structure appears to have point group symmetry 222 and, as also revealed by a tilt experiment, has the gross shape of a oval that displays a similar to 90 degrees twist in the body of the molecule. The reconstruction reveals a novel structure that consists of two Z-shaped components arranged in opposite orientation, These shapes are interconnected by two bridges at the elbow bends of the Z and by two archlike features that join their ends. The molecule has dimensions of similar to 190 x 125 x 120 Angstrom that encloses a 90 degrees twisted ellipsoidal shaped central cavity of 70 x 35 Angstrom. The cavity has four small openings arranged in a staggered configuration that extend to the outside. Serial slices of alpha(2)M and alpha(2)M-methylamine show that the bodies of the structures appear to be twisted in the opposite orientation, IL is proposed that the four thioester bonds in the native molecule are responsible for maintaining its twisted configuration and that their cleavage with methylamine results in the structure becoming twisted in the opposite orientation. A comparison of average images derived from unstained particles of monoclonal Fab-labeled alpha(2)M and alpha(2)M-methylamine is consistent with this proposal, This unusual change in the handedness of alpha(2)M may have an important role in the encapsulation of the proteinase. (C) 1996 Academic Press, Inc.