Human Molecular Genetics, Vol 5, 737-743, Copyright © 1996 by Oxford University Press
M Peltola, R Tikkanen, L Peltonen and A Jalanko
Aspartylglucosaminuria (AGU) is a lysosomal storage disease caused by
deficient activity of aspartylglucosaminidase (AGA). We report here a T214C
mutation leading to a Ser72Pro substitution in four Arab families. This is
the first naturally occurring AGU mutation involving an active-site amino
acid of this recently crystallized hydrolase and it seems to represent the
second most common AGU mutation worldwide. The intracellular consequences
of the Ser72Pro mutation were analyzed by transient expression in COS-1
cells and we were able to demonstrate that this active-site mutation most
probably does not destroy the enzyme activity per se, but specifically
prevents the proteolytic activation cleavage of AGA in the endoplasmic
reticulum (ER). The mutant enzyme is, however, folded correctly enough to
allow mannose-6- phosphorylation and targeting to lysosomes. The
overexpressed mutant enzyme remained inactive intracellularly, but the
secreted mutant precursor was proteolytically activated extracellularly,
resulting in a similar subunit composition to that in the wild-type AGA in
the ER. The partially activated mutant enzyme was endocytosed further by
the recipient cells. These data demonstrate that the proteolytic activation
of AGA can also occur extracellularly and suggest that the driving
mechanism of AGA precursor cleavage is autocatalytic.
ARTICLES
Ser72Pro active-site disease mutation in human lysosomal aspartylglucosaminidase: abnormal intracellular processing and evidence for extracellular activation
Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland.
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