![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
A more recent version of this article appeared on November 1, 2002
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on May 21, 2002
Revised on July 27, 2002
Accepted on August 8, 2002
1 Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, USA
* Corresponding author. E-mail address: hegder{at}mail.nih.gov.
The decisive events that direct a single polypeptide such as the prion protein (PrP) to be synthesized at the endoplasmic reticulum (ER) in both fully translocated and transmembrane forms are poorly understood. In this study, we demonstrate that the topologic heterogeneity of PrP is determined cotranslationally, while at the translocation channel. By evaluating sequential intermediates during PrP topogenesis, we find that signal sequence-mediated initiation of translocation results in an interaction between nascent PrP and ER chaperones, committing the N-terminus to the lumen. Synthesis of the transmembrane domain before completion of this step allows it to direct the generation of CtmPrP, a transmembrane form with its N-terminus in the cytosol. Thus, segregation of nascent PrP into different topologic configurations is critically dependent on the precise timing of signal-mediated initiation of N-terminus translocation. Consequently, this step could be experimentally tuned to modify PrP topogenesis, including complete reversal of the elevated CtmPrP caused by disease- associated mutations in the transmembrane domain. These results delineate the sequence of events involved in PrP biogenesis, explain the mechanism of action of CtmPrP-favoring mutations associated with neurodegenerative disease, and more generally, reveal that translocation substrates can be cotranslationally partitioned into multiple populations at the translocon.
This article has been cited by other articles:
|
|
 |
|
  A. Ashok and R. S. Hegde Retrotranslocation of Prion Proteins from the Endoplasmic Reticulum by Preventing GPI Signal Transamidation Mol. Biol. Cell, August 1, 2008; 19(8): 3463 - 3476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Amaya, T. Nakai, K. Komaru, M. Tsuneki, and S. Miura Cleavage of the ER-Targeting Signal Sequence of Parathyroid Hormone-related Protein is Cell-Type-Specific and Regulated in Cis by its Nuclear Localization Signal J. Biochem., April 1, 2008; 143(4): 569 - 579. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Marzi, A. Akhavan, G. Simmons, T. Gramberg, H. Hofmann, P. Bates, V. R. Lingappa, and S. Pohlmann The Signal Peptide of the Ebolavirus Glycoprotein Influences Interaction with the Cellular Lectins DC-SIGN and DC-SIGNR. J. Virol., July 1, 2006; 80(13): 6305 - 6317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Stewart and D. A. Harris A Transmembrane Form of the Prion Protein Is Localized in the Golgi Apparatus of Neurons J. Biol. Chem., April 22, 2005; 280(16): 15855 - 15864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Colombo, R. Longhi, S. Alcaro, F. Ortuso, T. Sprocati, A. Flora, and N. Borgese N-myristoylation determines dual targeting of mammalian NADH-cytochrome b(5) reductase to ER and mitochondrial outer membranes by a mechanism of kinetic partitioning J. Cell Biol., February 28, 2005; 168(5): 735 - 745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Buck and W. R. Skach Differential Stability of Biogenesis Intermediates Reveals a Common Pathway for Aquaporin-1 Topological Maturation J. Biol. Chem., January 7, 2005; 280(1): 261 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Seabury, R. L. Honeycutt, A. P. Rooney, N. D. Halbert, and J. N. Derr Prion protein gene (PRNP) variants and evidence for strong purifying selection in functionally important regions of bovine exon 3 PNAS, October 19, 2004; 101(42): 15142 - 15147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Stewart and D. A. Harris Mutational Analysis of Topological Determinants in Prion Protein (PrP) and Measurement of Transmembrane and Cytosolic PrP during Prion Infection J. Biol. Chem., November 14, 2003; 278(46): 45960 - 45968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Heller, K. F. Winklhofer, J. Heske, A. Reintjes, and J. Tatzelt Post-translational Import of the Prion Protein into the Endoplasmic Reticulum Interferes with Cell Viability: A CRITICAL ROLE FOR THE PUTATIVE TRANSMEMBRANE DOMAIN J. Biol. Chem., September 19, 2003; 278(38): 36139 - 36147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. T. Rutkowski, C. M. Ott, J. R. Polansky, and V. R. Lingappa Signal Sequences Initiate the Pathway of Maturation in the Endoplasmic Reticulum Lumen J. Biol. Chem., August 8, 2003; 278(32): 30365 - 30372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A Harris Trafficking, turnover and membrane topology of PrP: Protein function in prion disease Br. Med. Bull., June 1, 2003; 66(1): 71 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Fons, B. A. Bogert, and R. S. Hegde Substrate-specific function of the translocon-associated protein complex during translocation across the ER membrane J. Cell Biol., February 18, 2003; 160(4): 529 - 539. [Abstract] [Full Text] [PDF]
|
|
