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Titolo:
Analysis of a two-domain binding site for the urokinase-type plasminogen activator-plasminogen activator inhibitor-1 complex in low-density-lipoprotein-receptor-related protein
Autore:
Andersen, OM; Petersen, HH; Jacobsen, C; Moestrup, SK; Etzerodt, M; Andreasen, PA; Thogersen, HC;
Indirizzi:
Aarhus Univ, Gene Express Lab, Dept Mol & Struct Biol, DK-8000 Aarhus C, Denmark Aarhus Univ Aarhus Denmark C ol & Struct Biol, DK-8000 Aarhus C, Denmark Aarhus Univ, Lab Cellular Prot Sci, Dept Mol & Struct Biol, DK-8000 Aarhus, Denmark Aarhus Univ Aarhus Denmark DK-8000 Struct Biol, DK-8000 Aarhus, Denmark Aarhus Univ, Dept Med Biochem, DK-8000 Aarhus C, Denmark Aarhus Univ Aarhus Denmark C Dept Med Biochem, DK-8000 Aarhus C, Denmark
Titolo Testata:
BIOCHEMICAL JOURNAL
, volume: 357, anno: 2001,
parte:, 1
pagine: 289 - 296
SICI:
0264-6021(20010701)357:<289:AOATBS>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
GROWTH-FACTOR PRECURSOR; NMR SOLUTION STRUCTURE; CYSTEINE-RICH REPEAT; LDL-RECEPTOR; ALPHA-2-MACROGLOBULIN RECEPTOR; HIGH-AFFINITY; APOLIPOPROTEIN-E; LIGAND-BINDING; GENE FAMILY; 3-DIMENSIONAL STRUCTURE;
Keywords:
complement-type repeat; protein-protein interactions; receptor-associated protein;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
54
Recensione:
Indirizzi per estratti:
Indirizzo: Thogersen, HC Aarhus Univ, Gene Express Lab, Dept Mol & Struct Biol, Gustav Wieds Vej 10, DK-8000 Aarhus C, Denmark Aarhus Univ Gustav Wieds Vej 10 Aarhus Denmark C C, Denmark
Citazione:
O.M. Andersen et al., "Analysis of a two-domain binding site for the urokinase-type plasminogen activator-plasminogen activator inhibitor-1 complex in low-density-lipoprotein-receptor-related protein", BIOCHEM J, 357, 2001, pp. 289-296

Abstract

The low-density-lipoprotein-receptor (LDLR)-related protein (LRP) is composed of several classes of domains, including complement-type repeats (CR), which occur in clusters that contain binding sites for a multitude of different ligands. Each approximate to 40-residue CR domain contains three conserved disulphide linkages and an octahedral Ca2+ cage. LRP is a scavenging receptor for ligands from extracellular fluids, e.g. alpha (2)-macroglobulin(alpha M-2)-proteinase complexes. lipoprotein-containing particles and serine proteinase-inhibitor complexes, like the complex between urokinase-typeplasminogen activator (uPA) and the plasminogen activator inhibitor-1 (PAI-I). In the present study we analysed the interaction of the uPA-PAI-1 complex with an ensemble of fragments representing a complete overlapping set of two-domain fragments accounting for the ligand-binding cluster II (CR3-CR10) of LRP, By ligand blotting, solid-state competition analysis and surface-plasmon-resonance analysis, we demonstrate binding to multiple CR domains, but show a preferential interaction between the uPAPAI-1 complex and a two-domain fragment comprising CR domains 5 and 6 of LRP. We demonstrate thatsurface-exposed aspartic acid and tryptophan residues at identical positions in the two homologous domains, CR5 and CR6 (Asp(958.CR5), Asp(999.CR6), Trp(953.CR5) and Trp(994.CR6)), are critical for the binding of the complexas well as for the binding of the receptor-associated protein (RAP)- the folding chaperone/escort protein required for transport of LRP to the cell surface. Accordingly, the present work provides (1) an identification of a preferred binding site within LRP CR cluster II: (2) evidence that the uPA-PAI-1 binding sire involves residues from two adjacent protein domains; and (3) direct evidence identifying specific residues as important for the binding of uPa-PAI-1 as well as for the binding of RAP.

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Documento generato il 01/12/20 alle ore 07:01:12