Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.3.1.108 (
TAT
)
2,389
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Transmissible spongiform encephalopathies, including variant-Creutzfeldt-Jakob disease (vCJD) in humans and bovine spongiform encephalopathies in cattle, are fatal neurodegenerative disorders characterized by protein misfolding of the host cellular prion protein (
PrP
(C)) to the infectious scrapie form (
PrP
(Sc)). However, the mechanism that exogenous
PrP
(Sc) infects cells and where pathologic conversion of
PrP
(C) to the
PrP
(Sc) form occurs remains uncertain. Here we report that similar to the mechanism of HIV-1
TAT
-mediated peptide transduction, processed mature, full length
PrP
contains a conserved N-terminal cationic domain that stimulates cellular uptake by lipid raft-dependent, macropinocytosis. Inhibition of macropinocytosis by three independent means prevented cellular uptake of recombinant
PrP
; however, it did not affect recombinant
PrP
cell surface association. In addition, fusion of the cationic N-terminal
PrP
domain to a Cre recombinase reporter protein was sufficient to promote both cellular uptake and escape from the macropinosomes into the cytoplasm. Inhibition of macropinocytosis was sufficient to prevent conversion of
PrP
(C) to the pathologic
PrP
(Sc) form in N2a cells exposed to strain RML
PrP
(Sc) infected brain homogenates, suggesting that a critical determinant of
PrP
(C) conversion occurs following macropinocytotic internalization and not through mere membrane association. Taken together, these observations provide a cellular mechanism that exogenous pathological
PrP
(Sc) infects cells by lipid raft dependent, macropinocytosis.
...
PMID:Pathologic prion protein infects cells by lipid-raft dependent macropinocytosis. 1939 Jun 57
