The hemopexin and O-glycosylated domains tune gelatinase B/MMP-9 bioavailability via inhibition and binding to cargo receptors.
Gelatinase B/matrix metalloproteinase-9 (MMP-9), a key regulator and effector of immunity, contains a C-terminal hemopexin domain preceded by a unique linker sequence of approximately 64 amino acid residues. This linker sequence is demonstrated to be an extensively O-glycosylated (OG) domain with a compact three-dimensional structure. The OG and hemopexin domains have no influence on the cleavage efficiency of MMP-9 substrates. In contrast, the hemopexin domain contains a binding site for the cargo receptor low density lipoprotein receptor-related protein-1 (LRP-1). Furthermore, megalin/LRP-2 is identified as a new functional receptor for the hemopexin domain of MMP-9, able to mediate the endocytosis and catabolism of the enzyme. The OG domain is required to correctly orient the hemopexin domain for inhibition by TIMP-1 and internalization by LRP-1 and megalin. Therefore, the OG and hemopexin domains down-regulate the bioavailability of active MMP-9 and the interactions with the cargo receptors are proposed to be the original function of hemopexin domains in MMPs.
Van den Steen
Philippe E
PE
Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, B-3000, Belgium.
Van Aelst
Ilse
I
Hvidberg
Vibeke
V
Piccard
Helene
H
Fiten
Pierre
P
Jacobsen
Christian
C
Moestrup
Soren K
SK
Fry
Simon
S
Royle
Louise
L
Wormald
Mark R
MR
Wallis
Russell
R
Rudd
Pauline M
PM
Dwek
Raymond A
RA
Opdenakker
Ghislain
G