The low density lipoprotein receptor‐related protein (LRP) is a cell surface glycoprotein that binds and transports plasma lipoproteins enriched in apolipoprotein E. It is synthesized in the endoplasmic reticulum as a transmembrane glycosylated precursor that migrates with an apparent molecular mass of about 600 kd on SDS‐polyacrylamide gels. After it reaches the Golgi complex, the protein is cleaved to generate two subunits with apparent molecular masses of approximately 515 and 85 kd respectively. The larger NH2‐terminal alpha‐subunit lacks a membrane‐spanning region. It remains attached to the membrane through noncovalent association with the smaller COOH‐terminal beta‐subunit. Proteolysis occurs at the sequence RHRR, which resembles the sequence RKRR at the proteolytic site in the receptors for insulin and insulin‐like growth factor‐1 (IGF‐1), the only other cell surface receptors known to undergo proteolytic processing. Proteolysis of LRP occurs coincident with the conversion of the N‐linked carbohydrates to the mature endoglycosidase H‐resistant, neuraminidase‐sensitive form. Proteolysis is prevented by brefeldin A, which blocks transport to the Golgi complex. These data raise the possibility that LRP and the receptors for insulin and IGF‐1 are processed by a specific endoprotease that recognizes protein with extended basic sequences and resides in the trans‐Golgi complex or in post‐Golgi vesicles of the constitutive secretory pathway.

Proteolytic processing ofthe600kdlowdensity lipoprotein receptor-related protein (LRP) occursina trans-Golgi compartment

The α2-macroglobulin receptor and epithelial glycoprotein-330 : two giant receptors mediating endocytosis of multiple ligands

Imaging biological structures with the cryo atomic force microscope.

Mouse plasma cr-2-macroglobulin (ma2M) was isolated and the N-terminal amino-acid sequences determined after separation of the 165-kDa and 35-kDa subunits. These sequences were compared to the protein sequence predicted by the cDNA, which was cloned from a mouse liver library and sequenced. From these data it is evident that both subunits are encoded by one mRNA of approximately 5 kb expressed predominantly in liver. The smaller subunit, with the N-terminal sequence DLSSSDLT, comprises the C-terminal 257 residues of ma2M and is derived from a single-chain precursor probably by proteolytic processing at an arginine residue in the sequence PTRDLSS. Analysis of the predicted protein further showed all the salient features of a proteinase inhibitor of the macroglobulin family: a bait region that deviates from all known sequences in this family, a very conserved internal thiolester site and conserved cysteine residues and putative N-glycosylation sites. The synthesis of ma2M in adult liver was demonstrated by Northern blotting and in fetal liver by in-situ hybridization. Transient transfection of COS cells with the cDNA under control of a viral promoter demonstrated the secretion and partial processing of ma2M in the culture medium. In plasma the level of ma2M was found to be stable as expected for the murine counterpart of human plasma a-%-macroglobulin. The possibilities of using the mouse as a genetic model to study this proteinase inhibitor in vivo are discussed. Proteinase inhibitors of the a-2-macroglobulin (a2M) family continue to yield information on crucial aspects of the mechanism by which they bind proteinases and eliminate them from the circulation and from the extracellular spaces (for reviews see Van Leuven, 1982; Sottrup- Jensen, 1989; Delain et al., 1992). The widespread occurrence of these inhibitors, in widely different species like arthropods and mammals, their presence in different molecular forms in most species examined, their occurrence in blood, in other body fluids and in other compartments, like in eggs, their specific expression under different physiological conditions like infection (rat acute-phase a2M) or pregnancy (human pregnancy zone protein) are indications for an important role in vivo. This role, however, is far from being known in the same detail as the structure of these proteinase inhibitors. The similarity to complement components C3, C4 and C5 would indicate that these proteinase inhibitors are also essential parts of one or the other protective system. Their Correspondence to F. van Leuven, Center for Human Genetics,

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1992.tb17424.x

The primary sequence and the subunit structure of mouse alpha-2-macroglobulin, deduced from protein sequencing of the isolated subunits and from molecular cloning of the cDNA.

OBJECTIVE—Neutrophil elastase accounts for the ability of some fresh rheumatoid synovial fluids to degrade cartilage matrix in vitro. The aim of this study was to determine if enzyme activity could result from depletion of synovial fluid inhibitors or protection of the enzyme from inhibition.
METHODS—The ability of synovial fluids to inhibit porcine pancreatic elastase was investigated together with chemical pretreatments capable of inactivating alpha1 protease inhibitor (α1PI) or preventing formation of alpha2 macroglobulin (α2M) elastase complexes. Subsequently, complexes of human neutrophil elastase with α2M were prepared and applied to frozen sections of cartilage. Proteoglycan loss was quantified by alcian blue staining and scanning and integrating microdensitometry. Parallel studies were carried out using a low molecular weight chromogenic elastase substrate. The effects of α1PI and SF on these systems were investigated. Finally, synovial fluids were subjected to gel filtration and the fractions assayed for elastase activity. High molecular weight fractions were pooled, concentrated, and tested for their ability to degrade cartilage sections.
RESULTS—All synovial fluids reduced the activity of porcine pancreatic elastase, the inhibition mainly being attributable to α1PI, whereas remaining activity resulted from complexes of elastase with α2M. Complexes of human neutrophil elastase with α2M were shown to cause proteoglycan degradation in frozen sections of human articular cartilage. Alpha1PI prevented α2M elastase complexes from degrading cartilage but not the chromogenic substrate. The data suggested that α1PI does not inhibit elastase bound to α2M but sterically hinders the complex. However, only one of five synovial fluids was able to completely block the actions of α2M elastase complexes against cartilage. Gel filtration of rheumatoid synovial fluids showed elastase and cartilage degrading activity to be associated with fractions that contained α2M, and not with fractions expected to contain free enzyme.
CONCLUSIONS—The data suggest that synovial fluid α2M elastase complexes can degrade cartilage matrix in rheumatoid arthritis.

Keywords: alpha1 antitrypsin; alpha2 macroglobulin; glycosaminoglycans; neutrophil elastase; proteoglycans; synovial fluid

https://ard.bmj.com/content/annrheumdis/58/2/109.full.pdf

Destruction of articular cartilage by alpha2 macroglobulin elastase complexes: role in rheumatoid arthritis

Ultrastructure of alpha 2-macroglobulins.

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Ultrastructure of alpha 2-macroglobulins.