Misfolding of the Prion Protein at the Plasma Membrane Induces Endocytosis, Intracellular Retention and Degradation

Kiachopoulos, Sophia; Heske, Johanna; Tatzelt, Jörg; Winklhofer, Konstanze F.

doi:10.1111/j.1398-9219.2004.00185.x

Cited by 48 publications

(53 citation statements)

References 47 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Deletion of just four residues from the Nterminal polybasic region in PrP-⌬N did not prevent the protein moving laterally out of rafts on exposure of the cells to Cu 2+ but did prevent its endocytosis. Deletions of large regions of the unstructured N-terminus of PrP C [residues 27-89 (Kiachopoulos et al, 2004) and residues 23-90, 48-93 and 23-51 (Nunziante et al, 2003)] have been reported to disrupt the internalisation of PrP C , and point mutations within the Nterminal polybasic region disrupted the constitutive endocytosis of PrP C (Sunyach et al, 2003). However, none of these studies discriminated between the function of the polybasic region and that of the octapeptide repeats.…”

Section: Discussionmentioning

confidence: 92%

Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis

Taylor

Watt

Perera

et al. 2005

Journal of Cell Science

142

148

View full text Add to dashboard Cite

The cellular prion protein (PrPC) is essential for the pathogenesis and transmission of prion diseases. Although PrPC is known to be located in detergent-insoluble lipid rafts at the surface of neuronal cells, the mechanism of its internalisation is unclear, with both raft/caveolae-based and clathrin-mediated processes being proposed. We have investigated the mechanism of copper-induced internalisation of PrPC in neuronal cells by immunofluorescence microscopy, surface biotinylation assays and buoyant sucrose density gradient centrifugation in the presence of Triton X-100. Clathrin-mediated endocytosis was selectively blocked with tyrphostin A23, which disrupts the interaction between tyrosine motifs in the cytosolic domains of integral membrane proteins and the adaptor complex AP2, and a dominant-negative mutant of the adaptor protein AP180. Both these agents inhibited the copper-induced endocytosis of PrPC. Copper caused PrPC to move laterally out of detergent-insoluble lipid rafts into detergent-soluble regions of the plasma membrane. Using mutants of PrPC that lack either the octapeptide repeats or the N-terminal polybasic region, and a construct with a transmembrane anchor, we show that copper binding to the octapeptide repeats promotes dissociation of PrPC from lipid rafts, whereas the N-terminal polybasic region mediates its interaction with a transmembrane adaptor protein that engages the clathrin endocytic machinery. Our results provide an experimental basis for reconciling the apparently contradictory observations that the prion protein undergoes clathrin-dependent endocytosis despite being localised in lipid rafts. In addition, we have been able to assign distinct functions in the endocytic process to separate regions of the protein.

show abstract

Section: Discussionmentioning

confidence: 92%

Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis

Taylor

Watt

Perera

et al. 2005

Journal of Cell Science

142

148

View full text Add to dashboard Cite

show abstract

“…For the intracellular transduction of PrP c -STI1-mediated signaling, endocytosis of PrP c is required (Americo et al, 2007;Caetano et al, 2008). For this reason, a strong correlation between PrP c trafficking alterations and prion pathologies have been suggested in other studies (Borchelt et al, 1992;Kiachopoulos et al, 2004;Pimpinelli et al, 2005;Shyng et al, 1995). Lastly, a recent study has reported PrP c -independent functions of STI1 in cell proliferation (Arruda-Carvalho et al, 2007).…”

Section: Prp C Ligands and Intracellular Signalingmentioning

confidence: 91%

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

Nicolas

Gavı́n

Rı́o

2009

Brain Research Reviews

View full text Add to dashboard Cite

show abstract

“…pentosan polysulfate (21), copper (18), suramin (30), and phosphorothioate oligonucleotides (22), affect the intracellular localization of PrP C . Because various synthetic cTPs inhibit PrP Sc formation, we wondered if hemin, as a natural cTP and potential physiological ligand for PrP C , can also affect PrP C localization.…”

Section: Resultsmentioning

confidence: 99%

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

Lee

Raymond

Schoen

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Hemin (iron protoporphyrin IX) is a crucial component of many physiological processes acting either as a prosthetic group or as an intracellular messenger. Some unnatural, synthetic porphyrins have potent anti-scrapie activity and can interact with normal prion protein (PrP C ). These observations raised the possibility that hemin, as a natural porphyrin, is a physiological ligand for PrP C . Accordingly, we evaluated PrP C interactions with hemin. When hemin (3-10 M) was added to the medium of cultured cells, clusters of PrP C formed on the cell surface, and the detergent solubility of PrP C decreased. The addition of hemin also induced PrP C internalization and turnover. The ability of hemin to bind directly to PrP C was demonstrated by hemin-agarose affinity chromatography and UV-visible spectroscopy. Multiple hemin molecules bound primarily to the N-terminal third of PrP C , with reduced binding to PrP C lacking residues 34 -94. These hemin-PrP C interactions suggest that PrP C may participate in hemin homeostasis, sensing, and/or uptake and that hemin might affect PrP C functions.

show abstract

Misfolding of the Prion Protein at the Plasma Membrane Induces Endocytosis, Intracellular Retention and Degradation

Cited by 48 publications

References 47 publications

Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis

Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

Contact Info

Product

Resources

About