Activated terminal complement proteins C5b to C9 form the membrane attack c
omplex (MAC) pore. Insertion of the MAC into endothelial cell membranes cau
ses the release of growth factors that stimulate tissue growth and prolifer
ation. The complement regulatory membrane protein CD59 restricts MAC format
ion. Because increased cell proliferation characterizes the major chronic v
ascular complications of human diabetes and because increased glucose level
s in diabetes cause protein glycation and impairment of protein function, w
e investigated whether glycation could inhibit CD59. Glycation-inactivation
of CD59 would cause increased MAC deposition and MAC-stimulated cell proli
feration. Here, we report that (i) human CD59 is glycated in vivo, (ii) gly
cated human CD59 loses its MAC-inhibitory function, and (iii) inactivation
of CD59 increases MAC-induced growth factor release from endothelial cells.
We demonstrate by site-directed mutagenesis that residues K41 and H44 form
a preferential glycation motif in human CD59. The presence of this glycati
on motif in human CD59, but not in CD59 of other species, may help explain
the distinct propensity of humans to develop vascular proliferative complic
ations of diabetes.