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J Biol Chem, Vol. 274, Issue 2, 717-727, January 8, 1999

Domain Organization of the 39-kDa Receptor-associated Protein

Leonid V. MedvedDagger , Mary Migliorini§, Irina Mikhailenko§, Laura G. Barrientos, Miguel Llinás, and Dudley K. Strickland§**

From the Departments of § Vascular Biology and Dagger  Biochemistry, Holland Laboratory, American Red Cross, Rockville, Maryland 20855, the ** Department of Biochemistry and Molecular Biology and Institute for Biomedical Sciences, George Washington University Medical Center, Washington, D. C. 20037, and the  Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213

The 39-kDa receptor-associated protein (RAP) is an endoplasmic reticulum resident protein that binds to the low density lipoprotein receptor-related protein (LRP) as well as certain members of the low density lipoprotein receptor superfamily and antagonizes ligand binding. In order to identify important functional regions of RAP, studies were performed to define the domain organization and domain boundaries of this molecule. Differential scanning calorimetry (DSC) experiments revealed that the process of thermal denaturation of RAP is highly reversible and occurs in a broad temperature range with two well resolved heat absorption peaks. A good fit of the endotherm was obtained with four two-state transitions suggesting these many cooperative domains in the molecule. A number of recombinant fragments of RAP were expressed in bacteria, and their domain composition and stability were characterized by DSC, circular dichroism, and fluorescence spectroscopy. The results confirmed that RAP is composed of four independently folded domains, D1, D2, D3, and D4, that encompass residues 1-92, 93-163, 164-216, and 217-323, respectively. The first and the fourth domains preserved their structure and stability when isolated, whereas the compact structure of the fragment corresponding to D2 seems to be altered when isolated from the parent molecule. Isolated D3 was partially degraded during isolation from bacterial lysates. The isolated D4 was capable of binding with high affinity to LRP whereas neither D1 nor D2 bound. At the same time a fragment containing both D1 and D2 exhibited high affinity binding to LRP. These facts combined with the thermodynamic analysis of the melting process of the fragments containing D1 and D2 indicate that these two domains interact with each other and that the proper folding of the second domain into a native-like active conformation requires presence of the first domain.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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