Mechanism and significance of specific proteolytic cleavage of Reelin.
Reelin is a secreted glycoprotein essential for normal brain development and function. In the extracellular milieu, Reelin is subject to specific cleavage at two (N-t and C-t) sites. The N-t cleavage of Reelin is implicated in psychiatric and Alzheimer's diseases, but the molecular mechanism and physiological significance of this cleavage are not completely understood. Particularly, whether the N-t cleavage affects the signaling activity of Reelin remains controversial. Here, we show that the protease in charge of the N-t cleavage of Reelin requires the activity of certain proprotein convertase family for maturation and has strong affinity for heparin. By taking advantage of these observations, we for the first time succeeded in obtaining "Uncleaved" and "Completely Cleaved" Reelin proteins. The N-t cleavage splits Reelin into two distinct fragments and virtually abolishes its signaling activity. These findings provide an important biochemical basis for the function of Reelin proteolysis in brain development and function.
Kohno
Shiori
S
Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
Kohno
Takao
T
Nakano
Yoshimi
Y
Suzuki
Kenta
K
Ishii
Moe
M
Tagami
Hideaki
H
Baba
Atsushi
A
Hattori
Mitsuharu
M
D000590:Amino Acid Chloromethyl Ketones; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D045683:Furin / Q000037:antagonists & inhibitors / Q000378:metabolism; D006493:Heparin / Q000737:chemistry; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D000091042:Reelin Protein; C460143:decanoylRVKRchloromethylketone; C492739:hexaarginine amide; D006493:Heparin; D010447:Peptide Hydrolases; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D045683:Furin