Abstract

The Applicant is proposing to continue his studies of the structure of LRP, functional activity of this receptor, and modulation of expression. The Investigator has delineated some of the functions of this large ubiquitous cellular receptor, which intervenes in the internalization of some lipoproteins. In addition, the same receptor associates with a2-macroglobulin (a2M), and a2M-proteinase complexes and also with uPA and tPA of the fibrinolytic system. The major effort of this application is toward the characterization of the association of LRP with lipoprotein lipase and with b-VLDL and the biochemical reaction responsible for the internalization of this complex via the LRP receptor. Binding studies of LpL and of VLDL will be done using normal cell lines and cells deficient in LPR or LDL receptors. The contribution of other cellular surface components to the binding of ligands to LRP, such as proteoglycans, will also be analyzed by performing these studies in cells with low expression of proteoglycans.
A second Aim consists of elucidating the role of RAP, a 30-kDa protein that associates with LRP and seems to modify its functional activity.In his third specific Aim, the Investigator is planning to study some of the regulatory mechanisms involved in the expression of LPR and RAP by cellular components of the vessel wall.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM042581-06
Application #
2181499
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1989-07-01
Project End
1998-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
American National Red Cross
Department
Type
DUNS #
003255213
City
Washington
State
DC
Country
United States
Zip Code
20006

  Publications

Stefansson, S; Muhammad, S; Cheng, X F et al. (1998) Plasminogen activator inhibitor-1 contains a cryptic high affinity binding site for the low density lipoprotein receptor-related protein. J Biol Chem 273:6358-66
Zhang, J C; Sakthivel, R; Kniss, D et al. (1998) The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor regulates cell surface plasminogen activator activity on human trophoblast cells. J Biol Chem 273:32273-80
Mikhailenko, I; Krylov, D; Argraves, K M et al. (1997) Cellular internalization and degradation of thrombospondin-1 is mediated by the amino-terminal heparin binding domain (HBD). High affinity interaction of dimeric HBD with the low density lipoprotein receptor-related protein. J Biol Chem 272:6784-91
Morrot, A; Strickland, D K; Higuchi, M de L et al. (1997) Human T cell responses against the major cysteine proteinase (cruzipain) of Trypanosoma cruzi: role of the multifunctional alpha 2-macroglobulin receptor in antigen presentation by monocytes. Int Immunol 9:825-34
Argraves, K M; Kozarsky, K F; Fallon, J T et al. (1997) The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor. J Clin Invest 100:2170-81
Lucas, M; Iverius, P H; Strickland, D K et al. (1997) Lipoprotein lipase reduces secretion of apolipoprotein E from macrophages. J Biol Chem 272:13000-5
Kounnas, M Z; Church, F C; Argraves, W S et al. (1996) Cellular internalization and degradation of antithrombin III-thrombin, heparin cofactor II-thrombin, and alpha 1-antitrypsin-trypsin complexes is mediated by the low density lipoprotein receptor-related protein. J Biol Chem 271:6523-9
Kolodziej, S J; Schroeter, J P; Strickland, D K et al. (1996) The novel three-dimensional structure of native human alpha 2-macroglobulin and comparisons with the structure of the methylamine derivative. J Struct Biol 116:366-76
Waegemann, K; Soll, J (1996) Phosphorylation of the transit sequence of chloroplast precursor proteins. J Biol Chem 271:6545-54
Chen, H; Sottile, J; Strickland, D K et al. (1996) Binding and degradation of thrombospondin-1 mediated through heparan sulphate proteoglycans and low-density-lipoprotein receptor-related protein: localization of the functional activity to the trimeric N-terminal heparin-binding region of thrombospondin-1 Biochem J 318 ( Pt 3):959-63

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