RAP AS A MOLECULAR CHAPERONE/ESCORT PROTEIN FOR LRP

Project: Research project

Project Details

Description

The LDL receptor-related protein (LRP) is an extremely large (600,000 kDa)
single chain protein with four related extracellular domains that are in
turn composed of multiple (2, 8, 10, 11 respectively) cysteine-rich ligand
binding repeats. LRP has emerged as a unique endocytic receptor due to its
ability to bind and endocytose a number of structurally and functionally
distinct ligands. These include apolipoprotein E, 2-macroglobulin, tPA,
and urokinase-plasminogen activator. A 39kDa receptor-associated protein
(RAP) co-purifies with intracellular LRP and blocks ligand binding to LRP
in vitro. Preliminary data provided in this proposal demonstrate that the
different ligands bind to multiple and distinct regions on LRP and LRP
binding sites on RAP. In addition, many cells that synthesize LRP and RAP
also synthesize ligands for the receptor, which can prevent the correct
folding of LRP if they associate to early. The P.I. hypothesizes that RAP
serves a chaperoning function in the folding and proper trafficking of LRP
by binding it and preventing premature association with ligand.
Experiments are proposed to elucidate the molecular mechanism by which RAP
interacts with LRP, explore the structural features of RAP by solving its
crystal structure, determine the role of RAP as a folding chaperone using
in vivo and in vitro methods, and define the trafficking of RAP and LRP
both as individual molecules and interacting complexes.
StatusFinished
Effective start/end date1/1/9812/31/03

ASJC

  • Medicine(all)