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Inactivation of the proximal NPXY motif impairs early steps in LRP1 biosynthesis

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Abstract

The proximal NPXY and distal NPXYXXL motifs in the intracellular domain of LRP1 play an important role in regulation of the function of the receptor. The impact of single and double inactivating knock-in mutations of these motifs on receptor maturation, cell surface expression, and ligand internalization was analyzed in mutant and control wild-type mice and MEFs. Single inactivation of the proximal NPXY or in combination with inactivation of the distal NPXYXXL motif are both shown to be associated with an impaired maturation and premature proteasomal degradation of full-length LRP1. Therefore, only a small mature LRP1 pool is able to reach the cell surface resulting indirectly in severe impairment of ligand internalization. Single inactivation of the NPXYXXL motif revealed normal maturation, but direct impairment of ligand internalization. In conclusion, the proximal NPXY motif proves to be essential for early steps in the LRP1 biosynthesis, whereas NPXYXXL appears rather relevant for internalization.

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Acknowledgments

This work was supported by the “Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO)”, SAO-FRMA/2004/2006 and VIB to A.R., the Concerted Actions Program (GOA/2006-2010) to P.Z. and A.R., VIB, the SAO-FRMA/2006 and IAP P6/43 to W.A. and the “Deutsche Forschungsgemeinschaft” Grant Pi 379 3-3 and “Bundesministerium für Forschung und Bilding” Grant 01GI0719 to C.P.. The research was also funded by PhD grants of the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen) to S.R. and P.G. We thank Annick Lauwers, Nathalie Feyaerts and Leen Verbeek for technical assistance.

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Authors and Affiliations

  1. Laboratory for Experimental Mouse Genetics, Center for Human Genetics, KU Leuven, Herestraat 49, bus 602, 3000, Leuven, Belgium

    Sara M. Reekmans, Philip L. S. M. Gordts & Anton J. M. Roebroek

  2. Laboratory for Signal Integration in Cell Fate Decision, Center for Human Genetics, KU Leuven, Leuven, Belgium

    Pascale Zimmermann

  3. Laboratory of Membrane Trafficking, Center for Human Genetics, KU Leuven, Leuven, Belgium

    Wim Annaert

  4. Laboratory for Experimental Mouse Genetics, Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium

    Sara M. Reekmans, Philip L. S. M. Gordts & Anton J. M. Roebroek

  5. Laboratory of Membrane Trafficking, Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium

    Wim Annaert

  6. Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany

    Sascha Weggen

  7. Molecular Neurodegeneration, Department of Physiological Chemistry and Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55099, Mainz, Germany

    Thorsten Pflanzner, Simone Isbert & Claus U. Pietrzik

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  1. Sara M. Reekmans
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Correspondence to Anton J. M. Roebroek or Claus U. Pietrzik.

Additional information

S. M. Reekmans, T. Pflanzer and P. L. S. M. Gordts are co-first authors. A. J. M. Roebroek and C. U. Pietrzik are co-last authors.

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Reekmans, S.M., Pflanzner, T., Gordts, P.L.S.M. et al. Inactivation of the proximal NPXY motif impairs early steps in LRP1 biosynthesis. Cell. Mol. Life Sci. 67, 135–145 (2010). https://doi.org/10.1007/s00018-009-0171-7

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  • DOI: https://doi.org/10.1007/s00018-009-0171-7

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