scholarly journals Peculiaries of interactions between proteins of the macroglobulin family and with the endocytic receptors (a possible mechanism of transmembrane transfer)

2011 ◽  
Vol 57 (1) ◽  
pp. 106-113
Author(s):  
V.N. Zorina ◽  
R.M. Zorina ◽  
N.A. Zorin
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Receptor Associated Protein ◽  
Leading Role ◽  
The Family ◽  
Density Lipoprotein Receptor ◽  
A Cell ◽  
Series Of Experiments ◽  
First Time ◽  
Lipoprotein Receptor Related Protein

We have conducted a series of experiments, for specification of mechanisms which proteins of the macroglobulin family deliver regulatory substances inside of a cells. We have shown that all members of the family are not only compete for binding to proteinases, but also can interact with each other. We have confirmed that only a complex of alpha-2-macroglobulin (α2-MG) with proteinase is capable to react with the major endocytic receptor (low-density lipoprotein receptor-related protein, LRP). For the first time we have demonstrated, that interaction of α2-MG firstly with proteinase, and then with LRP provokes a progressive conformational consolidation of the multicomplex, which is accompanied by a paradoxical increase of the electrophoretic mobility in comparison with native α2-MG. We suggest that such stepwise conformational consolidation, together with earlier demonstrated charge neutralization (versus pI of internal environments) after interaction firstly with proteinase, and then with LRP, components of is the key moment of the mechanism of transmembrane transfer. Taking into account, that α2-MG transfers a broad spectrum of protein regulators, and interacts not only with LRP, but also with a signal receptor (grp78), and also can regulate (under certain conditions) both own synthesis, and synthesis of LRP and its blocker (receptor - associated protein, RAP), we suggest that this main member of the macroglobulin family plays a leading role in the regulation of intercellular interactions and in the transmission of signal inside of a cell.

scholarly journals The Low-Density Lipoprotein Receptor-Related Protein (LRP) Mediates Clearance of Coagulation Factor Xa In Vivo

Blood ◽  
1998 ◽  
Vol 91 (2) ◽  
pp. 555-560 ◽  
Author(s):  
Masaaki Narita ◽  
Amy E. Rudolph ◽  
Joseph P. Miletich ◽  
Alan L. Schwartz
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Lipoprotein Receptor ◽  
Factor X ◽  
Receptor Associated Protein ◽  
Density Lipoprotein Receptor ◽  
Lipoprotein Receptor Related Protein

Abstract Blood coagulation factor X plays a pivotal role in the clotting cascade. When administered intravenously to mice, the majority of activated factor X (factor Xa) binds to α2-macroglobulin (α2M) and is rapidly cleared from the circulation into liver. We show here that the low-density lipoprotein receptor-related protein (LRP) is responsible for factor Xa catabolism in vivo. Mice overexpressing a 39-kD receptor-associated protein that binds to LRP and inhibits its ligand binding activity displayed dramatically prolonged plasma clearance of 125I-factor Xa. Preadministration of α2M-proteinase complexes (α2M*) also diminished the plasma clearance of125I-factor Xa in a dose-dependent fashion. The clearance of preformed complexes of 125I-factor Xa and α2M was similar to that of 125I-factor Xa alone and was also inhibited by mice overexpressing a 39-kD receptor-associated protein. These results thus suggest that, in vivo, factor Xa is metabolized via LRP after complex formation with α2M.

scholarly journals Receptor-associated protein (RAP) has two high-affinity binding sites for the low-density lipoprotein receptor-related protein (LRP): consequences for the chaperone functions of RAP

2009 ◽  
Vol 421 (2) ◽  
pp. 273-282 ◽  
Author(s):  
Jan K. Jensen ◽  
Klavs Dolmer ◽  
Christine Schar ◽  
Peter G. W. Gettins
Keyword(s):  
Binding Sites ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Affinity Binding ◽  
Lipoprotein Receptor ◽  
Related Protein ◽  
Receptor Associated Protein ◽  
High Affinity ◽  
Density Lipoprotein Receptor ◽  
Lipoprotein Receptor Related Protein

RAP (receptor-associated protein) is a three domain 38 kDa ER (endoplasmic reticulum)-resident protein that is a chaperone for the LRP (low-density lipoprotein receptor-related protein). Whereas RAP is known to compete for binding of all known LRP ligands, neither the location, the number of binding sites on LRP, nor the domains of RAP involved in binding is known with certainty. We have systematically examined the binding of each of the three RAP domains (D1, D2 and D3) to tandem and triple CRs (complement-like repeats) that span the principal ligand-binding region, cluster II, of LRP. We found that D3 binds with low nanomolar affinity to all (CR)2 species examined. Addition of a third CR domain increases the affinity for D3 slightly. A pH change from 7.4 to 5.5 gave only a 6-fold increase in Kd for D3 at 37 °C, whereas temperature change from 22 °C to 37 °C has a similar small effect on affinity, raising questions about the recently proposed D3-destabilization mechanism of RAP release from LRP. Surprisingly, and in contrast to literature suggestions, D1 and D2 also bind to most (CR)2 and (CR)3 constructs with nanomolar affinity. Although this suggested that there might be three high-affinity binding sites in RAP for LRP, studies with intact RAP showed that only two binding sites are available in the intact chaperone. These findings suggest a new model for RAP to function as a folding chaperone and also for the involvement of YWTD domains in RAP release from LRP in the Golgi.

Sign in / Sign up

Export Citation Format

Share Document