Disrupted recycling of the low density lipoprotein receptor by PCSK9 is not mediated by residues of the cytoplasmic domain |
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| Authors: | Thea Bismo Strøm Øystein L. Holla Kristian Tveten Jamie Cameron Knut Erik Berge Trond P. Leren |
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| Affiliation: | 1. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi''an 710032, China;2. Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang 110016, China;3. Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China;4. Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi''an 710038, China;5. Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi''an 710038, China;6. Department of Cardiology, Graduate School, Third Military Medical University, Chongqing 400038, China;7. Center for Translational Medicine, Temple University School of Medicine, Philadelphia 19104, USA;8. Department of Surgery, Rutgers University Robert Wood Johnson Medical School, New Brunswick 08904, USA;1. Human Assisted Reproduction Ireland, Dublin, Ireland;2. Royal College of Surgeons in Ireland, Dublin, Ireland;3. Rotunda Hospital, Dublin, Ireland |
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| Abstract: | Proprotein convertase subtilisin/kexin type 9 (PCSK9) post-translationally regulates the number of cell-surface low density lipoprotein receptors (LDLR). This is accomplished by the ability of PCSK9 to mediate degradation of the LDLR. The underlying mechanism involves binding of secreted PCSK9 to the epidermal growth factor-like repeat A of the extracellular domain of the LDLR at the cell surface, followed by lysosomal degradation of the internalized LDLR:PCSK9 complex. However, the mechanism by which the normal recycling of the LDLR is disrupted by PCSK9, remains to be determined. In this study we have investigated the role of the cytoplasmic domain of the LDLR for this process. This has been done by studying the ability of a mutant LDLR (K811X-LDLR) which lacks the cytoplasmic domain, to be degraded by PCSK9. We show that this mutant receptor is degraded by PCSK9. Thus, the machinery which directs the LDLR:PCSK9 complex to the lysosomes for degradation, does not interact with the cytoplasmic domain of the LDLR. |
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