Low Density Lipoprotein Receptor-related Protein 1 (LRP1)-mediated Endocytic Clearance of a Disintegrin and Metalloproteinase with Thrombospondin Motifs-4 (ADAMTS-4)

Yamamoto, Kazuhiro; Owen, Kathryn; Parker, Andrew E.; Scilabra, Simone D.; Dudhia, Jayesh; Strickland, Dudley K.; Troeberg, Linda; Nagase, Hideaki

doi:10.1074/jbc.m113.545376

Cited by 77 publications

(91 citation statements)

References 66 publications

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“…plexes (4), we now know that LRP1 recognizes numerous ligands, including lipoproteins, matrix proteins, growth factors (1,2,5,6), and extracellular proteases (7)(8)(9)(10)(11). Deletion of the Lrp1 gene in mice results in early embryonic lethality at E13.5 (12,13) due to extensive hemorrhaging resulting from a failure to recruit and maintain vascular smooth muscle cells and pericytes in the vessels.…”

mentioning

confidence: 99%

High Affinity Binding of the Receptor-associated Protein D1D2 Domains with the Low Density Lipoprotein Receptor-related Protein (LRP1) Involves Bivalent Complex Formation

Prasad¹,

Young²,

Strickland

2016

Journal of Biological Chemistry

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The LDL receptor-related protein 1 (LRP1) is a large endocytic receptor that binds and mediates the endocytosis of numerous structurally diverse ligands. Currently, the basis for ligand recognition by LRP1 is not well understood. LRP1 requires a molecular chaperone, termed the receptor-associated protein (RAP), to escort the newly synthesized receptor from the endoplasmic reticulum to the Golgi. RAP is a three-domain protein that contains the following two high affinity binding sites for LRP1: one is located within domains 1 and 2, and one is located in its third domain. Studies on the interaction of the RAP third domain with LRP1 reveal critical contributions by lysine 256 and lysine 270 for this interaction. From these studies, a model for ligand recognition by this class of receptors has been proposed. Here, we employed surface plasmon resonance to investigate the binding of RAP D1D2 to LRP1. Our results reveal that the high affinity of D1D2 for LRP1 results from avidity effects mediated by the simultaneous interactions of lysine 60 in D1 and lysine 191 in D2 with sites on LRP1 to form a bivalent D1D2-LRP1 complex. When lysine 60 and 191 are both mutated to alanine, the binding of D1D2 to LRP1 is ablated. Our data also reveal that D1D2 is able to bind to a second distinct site on LRP1 to form a monovalent complex. The studies confirm the canonical model for ligand recognition by this class of receptors, which is initiated by pairs of lysine residues that dock into acidic pockets on the receptor.The LDL receptor-related protein 1 (LRP1) is a member of the LDL receptor family and is a highly efficient endocytic and signal-transducing receptor that plays an important role in vascular development, lipoprotein metabolism, and inflammation (1-3). Originally identified as the hepatic receptor responsible for the removal of ␣ 2 -macroglobulin (␣ 2 M) 3 -protease complexes (4), we now know that LRP1 recognizes numerous ligands, including lipoproteins, matrix proteins, growth factors (1, 2, 5, 6), and extracellular proteases (7-11). Deletion of the Lrp1 gene in mice results in early embryonic lethality at E13.5 (12, 13) due to extensive hemorrhaging resulting from a failure to recruit and maintain vascular smooth muscle cells and pericytes in the vessels. Selective deletion of LRP1 in vascular smooth muscle cells (smLRP1 Ϫ/Ϫ mice) reveals that LRP1 protects against the development of atherosclerosis by attenuating PDGF receptor activation (14, 15) and prevents formation of aneurysms (11, 16) in part by regulating the levels of proteases that are known to degrade matrix components (11).The efficient delivery of LRP1 and certain other members of the LDL receptor family to the cell surface require their association with a 39-kDa protein termed the receptor-associated protein (RAP). RAP was initially identified when it co-purified with LRP1 (17,18). Subsequent work demonstrated that RAP binds tightly to LRP1 and prevents ligands from associating with this receptor (19,20). In the endoplasmic reticulum (ER), RAP functions a...

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mentioning

confidence: 99%

High Affinity Binding of the Receptor-associated Protein D1D2 Domains with the Low Density Lipoprotein Receptor-related Protein (LRP1) Involves Bivalent Complex Formation

Prasad¹,

Young²,

Strickland

2016

Journal of Biological Chemistry

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confidence: 81%

“…Previous studies have shown that the C-terminal ancillary domains of TS4 and TS5 govern the specificity of the enzymes by modulating substrate binding (18,19,23) and internalization via lipoprotein receptor-related protein receptors (24,25). The results of studies in HTB-94 chondrosarcoma cells suggest that the CysR domain helps localize TS5 in the extracellular matrix (19), whereas in TS4, the spacer domain is thought to mediate matrix binding (26 -29 with thrombospondin motifs; Cat, catalytic; CysR, cysteine-rich; Dis, disintegrin; het, heterozygous; mBSA, methylated BSA; MMP, matrix metalloproteinase; MS, mass spectrometry; Pro, N-terminal prodomain; Sp, spacer domain; TS; thrombospondin-type 1 domains; TS5⌬cat, catalytically inactive Adamts5 with an in-frame deletion of exon 3; TS5 null, Adamts5 deficiency created by substitution of exon 2 for an IRES-lacZ-pgk neomycin (Neo) resistance cassette; TS5-FLAG, ADAMTS5 with a C-terminal FLAG tag; TS5-Myc, ADAMTS5 with a C-terminal Myc tag.…”

mentioning

confidence: 99%

A Disintegrin and Metalloproteinase with Thrombospondin Motifs-5 (ADAMTS-5) Forms Catalytically Active Oligomers

Kosasih

Last

Rogerson

et al. 2016

Journal of Biological Chemistry

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The metalloproteinase ADAMTS-5 (A disintegrin and metalloproteinase with thrombospondin motifs) degrades aggrecan, a proteoglycan essential for cartilage structure and function. ADAMTS-5 is the major aggrecanase in mouse cartilage, and is also likely to be the major aggrecanase in humans. ADAMTS-5 is a multidomain enzyme, but the function of the C-terminal ancillary domains is poorly understood. We show that mutant ADAMTS-5 lacking the catalytic domain, but with a full suite of ancillary domains inhibits wild type ADAMTS activity, in vitro and in vivo, in a dominant-negative manner. The data suggest that mutant ADAMTS-5 binds to wild type ADAMTS-5; thus we tested the hypothesis that ADAMTS-5 associates to form oligomers. Co-elution, competition, and in situ PLA experiments using full-length and truncated recombinant ADAMTS-5 confirmed that ADAMTS-5 molecules interact, and showed that the catalytic and disintegrin-like domains support these intermolecular interactions. Cross-linking experiments revealed that recombinantADAMTS-5formedlarge,reduction-sensitiveoligomers with a nominal molecular mass of ϳ400 kDa. The oligomers were unimolecular and proteolytically active. ADAMTS-5 truncates comprising the disintegrin and/or catalytic domains were able to competitively block full-length ADAMTS-5-mediated aggrecan cleavage, measured by production of the G1-EGE 373 neoepitope. These results show that ADAMTS-5 oligomerization is required for full aggrecanase activity, and they provide evidence that blocking oligomerization inhibits ADAMTS-5 activity. The data identify the surface provided by the catalytic and disintegrin-like domains of ADAMTS-5 as a legitimate target for the design of aggrecanase inhibitors.ADAMTS-5 (TS5) is one member of a family of secreted, multidomain, zinc-dependent proteinases known as A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS).2 TS5 is a major aggrecan-degrading enzyme (aggrecanase) (1) mediating proteolysis and loss of aggrecan from articular cartilage in arthritic diseases. TS5 inhibitors are currently in development for arthritis therapies (2, 3), although ADAMTS-4 (TS4) might also have a role in human joint disease (4 -6). LGHG (7, 8). Fragments arising from proteolysis at these sites have been detected in cartilage and synovial fluids from patients with arthritic diseases including rheumatoid arthritis, osteoarthritis, and juvenile idiopathic arthritis (9 -12).TS5 is a multidomain enzyme comprising an N-terminal pro (Pro)-domain, a catalytic (Cat) domain, a disintegrin (Dis)-like domain, two thrombospondin (TS)-type 1 motifs, a cysteinerich (CysR) region, and a spacer (Sp) domain as reviewed previously (13-15). It is expressed as a zymogen that requires cleavage by pro-protein convertases (16, 17) at a polyarginine consensus sequence to remove the pro-domain. Further processing at the C terminus by autocatalysis gives rise to multiple forms of TS5, and recombinant C-terminal truncates have altered enzyme activity and substrate specificity (18,19). The active and ...

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“…Subsequently, the disappearance was shown to be due to endocytosis of MMP-13 by LRP1 with the assistance of a 170 kDa MMP-13-specific receptor [59]. Other metalloproteinases currently known to be endocytosed by LRP1 are MMP-9 [60], MMP-9-TIMP-1 complexes [61], MMP-2-thrombospondin 2 complexes [62], proMMP-2-TIMP-2 complexes [63], ADAMTS-4 [64] and ADAMTS-5 [65]. In addition, TIMP-1 [66], TIMP-2 [67] and TIMP-3 [68] can be endocytosed by LRP1.…”

Section: Regulation Of Metalloproteinases and Timps By Lrp1mentioning

confidence: 96%

Extracellular regulation of metalloproteinases

2015

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Matrix metalloproteinases (MMPs) and adamalysin-like metalloproteinase with thrombospondin motifs (ADAMTSs) belong to the metzincin superfamily of metalloproteinases and they play key roles in extracellular matrix catabolism, activation and inactivation of cytokines, chemokines, growth factors, and other proteinases at the cell surface and within the extracellular matrix. Their activities are tightly regulated in a number of ways, such as transcriptional regulation, proteolytic activation and interaction with tissue inhibitors of metalloproteinases (TIMPs). Here, we highlight recent studies that have illustrated novel mechanisms regulating the extracellular activity of these enzymes. These include allosteric activation of metalloproteinases by molecules that bind outside the active site, modulation of location and activity by interaction with cell surface and extracellular matrix molecules, and endocytic clearance from the extracellular milieu by low-density lipoprotein receptor-related protein 1 (LRP1).

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Low Density Lipoprotein Receptor-related Protein 1 (LRP1)-mediated Endocytic Clearance of a Disintegrin and Metalloproteinase with Thrombospondin Motifs-4 (ADAMTS-4)

Cited by 77 publications

References 66 publications

High Affinity Binding of the Receptor-associated Protein D1D2 Domains with the Low Density Lipoprotein Receptor-related Protein (LRP1) Involves Bivalent Complex Formation

High Affinity Binding of the Receptor-associated Protein D1D2 Domains with the Low Density Lipoprotein Receptor-related Protein (LRP1) Involves Bivalent Complex Formation

A Disintegrin and Metalloproteinase with Thrombospondin Motifs-5 (ADAMTS-5) Forms Catalytically Active Oligomers

Extracellular regulation of metalloproteinases

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