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J. Biol. Chem., Vol. 278, Issue 11, 9370-9377, March 14, 2003

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Low Density Lipoprotein Receptor-related Protein and Factor IXa Share Structural Requirements for Binding to the A3 Domain of Coagulation Factor VIII^*

Niels Bovenschen, Ria C. Boertjes, Gunny van Stempvoort, Jan Voorberg, Peter J. Lenting^§, Alexander B. Meijer, and Koen Mertens^¶

From the  Department of Plasma Proteins, Sanquin Research at CLB, 1066 CX Amsterdam, The Netherlands and the ^¶ Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CA Utrecht, The Netherlands

Low-density lipoprotein receptor-related protein (LRP) is an endocytic receptor that binds multiple distinct ligands, including blood coagulation factor VIII (FVIII). FVIII is a heterodimeric multidomain protein that consists of a heavy chain (domains A1, a1, A2, a2, and B) and a light chain (domains a3, A3, C1, and C2). Both chains contribute to high-affinity interaction with LRP. One LRP-interactive region has previously been located in the C2 domain, but its affinity is low in comparison with that of the entire FVIII light chain. We now have compared a variety of FVIII light chain derivatives with the light chain of its homolog FVa for LRP binding. In surface plasmon resonance studies employing LRP cluster II, the FVa and FVIII light chains proved different in that only FVIII displayed high-affinity binding. Because the FVIII a3-A3-C1 fragment was effective in associating with LRP, this region was explored for structural elements that are exposed but not conserved in FV. Competition studies using synthetic peptides suggested that LRP binding involves the FVIII-specific region Lys¹⁸⁰⁴-Ala¹⁸³⁴ in the A3 domain. In line with this observation, LRP binding was inhibited by a recombinant antibody fragment that specifically binds to the FVIII sequence Glu¹⁸¹¹-Lys¹⁸¹⁸. The role of this sequence in LRP binding was further tested using a FVIII/FV chimera in which sequence Glu¹⁸¹¹-Lys¹⁸¹⁸ was replaced with the corresponding sequence of FV. Although this chimera still displayed residual binding to LRP cluster II, its affinity was reduced. This suggests that multiple sites in FVIII contribute to high-affinity LRP binding, one of which is the FVIII A3 domain region Glu¹⁸¹¹-Lys¹⁸¹⁸. This suggests that LRP binding to the FVIII A3 domain involves the same structural elements that also contribute to the assembly of FVIII with FIXa.

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