A pathogenic PrP mutation and doppel interfere with polarized sorting of the prion protein.
Several proteins linked to neurodegenerative diseases, such as the beta-amyloid precursor protein, amyloid beta-peptide, beta-secretase, and tau, undergo selective polarized sorting. We investigated polarized sorting of the mammalian prion protein (PrP(C)) and its homologue doppel (Dpl). In contrast to Dpl, which accumulates on the apical surface, PrP(C) is targeted selectively to the basolateral side in Madin-Darby canine kidney cells. An extensive deletion and domain swapping analysis revealed that the internal hydrophobic domain (HD) of PrP (amino acids 113-133) confers basolateral sorting in a dominant manner. PrP mutants lacking the HD are sorted apically, while Dpl chimeras containing the HD of PrP are directed to the basolateral membrane. Furthermore, a pathogenic PrP missense mutation within the HD leads to aberrant apical sorting of PrP as well.
Uelhoff
Armgard
A
Adolf Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, 80336 Munich, Germany.
Tatzelt
Jörg
J
Aguzzi
Adriano
A
Winklhofer
Konstanze F
KF
Haass
Christian
C
D000818:Animals; D002460:Cell Line; D016764:Cell Polarity; D004285:Dogs; D058851:GPI-Linked Proteins; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D009154:Mutation / Q000235:genetics*; D017096:Prion Diseases / Q000235:genetics*; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000502:physiology; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics
D058851:GPI-Linked Proteins; D011328:Prions; C122036:Prnd protein, mouse; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins