Molecular basis for a link between complement and the vascular complications of diabetes.
Activated terminal complement proteins C5b to C9 form the membrane attack complex (MAC) pore. Insertion of the MAC into endothelial cell membranes causes the release of growth factors that stimulate tissue growth and proliferation. The complement regulatory membrane protein CD59 restricts MAC formation. Because increased cell proliferation characterizes the major chronic vascular complications of human diabetes and because increased glucose levels in diabetes cause protein glycation and impairment of protein function, we investigated whether glycation could inhibit CD59. Glycation-inactivation of CD59 would cause increased MAC deposition and MAC-stimulated cell proliferation. Here, we report that (i) human CD59 is glycated in vivo, (ii) glycated 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 glycation motif in human CD59, but not in CD59 of other species, may help explain the distinct propensity of humans to develop vascular proliferative complications of diabetes.
Acosta
J
J
Laboratory for Membrane Transport, Harvard Medical School, 240 Longwood Avenue, C1-607, Boston, MA 02115, USA.
Hettinga
J
J
Flückiger
R
R
Krumrei
N
N
Goldfine
A
A
Angarita
L
L
Halperin
J
J
D000595:Amino Acid Sequence; D000818:Animals; D018957:CD59 Antigens / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D016466:CHO Cells; D002478:Cells, Cultured; D003001:Cloning, Molecular; D015938:Complement Membrane Attack Complex / Q000502:physiology*; D006224:Cricetinae; D003925:Diabetic Angiopathies / Q000235:genetics / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D004912:Erythrocytes / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology; D006031:Glycosylation; D006168:Guinea Pigs; D006801:Humans; D020014:K562 Cells; D051379:Mice; D051381:Rats; D012266:Ribose / Q000494:pharmacology; D016415:Sequence Alignment; D014162:Transfection; D014471:Umbilical Veins
D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D012266:Ribose; D005947:Glucose