title: The hemopexin and O-glycosylated domains tune gelatinase B/MMP-9 bioavailability via inhibition and binding to cargo receptors.
abstract: 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.
authors: Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, B-3000, Belgium.
authors: Philippe E
authors: PE
authors: Van den Steen
authors: Ilse
authors: I
authors: Van Aelst
authors: Vibeke
authors: V
authors: Hvidberg
authors: Helene
authors: H
authors: Piccard
authors: Pierre
authors: P
authors: Fiten
authors: Christian
authors: C
authors: Jacobsen
authors: Soren K
authors: SK
authors: Moestrup
authors: Simon
authors: S
authors: Fry
authors: Louise
authors: L
authors: Royle
authors: Mark R
authors: MR
authors: Wormald
authors: Russell
authors: R
authors: Wallis
authors: Pauline M
authors: PM
authors: Rudd
authors: Raymond A
authors: RA
authors: Dwek
authors: Ghislain
authors: G
authors: Opdenakker