THE NOVEL 3-DIMENSIONAL STRUCTURE OF NATIVE HUMAN ALPHA(2)-MACROGLOBULIN AND COMPARISONS WITH THE STRUCTURE OF THE METHYLAMINE DERIVATIVE

A three-dimensional reconstruction of alpha(2)-macroglobulin for (alph a(2)M) was computed from stain images. The structure appears to have p oint group symmetry 222 and, as also revealed by a tilt experiment, ha s the gross shape of a oval that displays a similar to 90 degrees twis t in the body of the molecule. The reconstruction reveals a novel stru cture that consists of two Z-shaped components arranged in opposite or ientation, 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 e ncloses a 90 degrees twisted ellipsoidal shaped central cavity of 70 x 35 Angstrom. The cavity has four small openings arranged in a stagger ed configuration that extend to the outside. Serial slices of alpha(2) M and alpha(2)M-methylamine show that the bodies of the structures app ear to be twisted in the opposite orientation, IL is proposed that the four thioester bonds in the native molecule are responsible for maint aining its twisted configuration and that their cleavage with methylam ine results in the structure becoming twisted in the opposite orientat ion. A comparison of average images derived from unstained particles o f monoclonal Fab-labeled alpha(2)M and alpha(2)M-methylamine is consis tent with this proposal, This unusual change in the handedness of alph a(2)M may have an important role in the encapsulation of the proteinas e. (C) 1996 Academic Press, Inc.