|
Regulation
of Protein Translocation Across the Endoplasmic Reti culum
(ER) Membrane
The translocation of protein domains across the membrane of the ER is
often assumed to be determined solely by the presence or absence of topogenic
sequences such as signal sequences or stop transfer sequences in the coding
region. But in some cases, sequences in nascent proteins that may serve
as stop transfer sequences are found to be fully translocated, depending
on the presence of transacting factors in the cytosol, membrane and lumen.
These have been termed Translocation Accessory Factors (TrAFs).
Our lab has been studying the biogenesis of diverse proteins which share
in common only that they utilize some form of translocational regulation.
Perhaps not coincidentally, these proteins include molecules that have
been implicated in a variety of human diseases, including the prion protein,
apolipoprotein B, cystic fibrosis transmembrane regulator (CFTR) and the
multidrug resistance p-glycoprotein (MDR). Our studies suggest that i)
translocation across the ER is an important site of regulation during
the biogenesis of each of these proteins, ii) at least some human diseases
appear to occur as a result of aberrant translocational regulation, and
iii) in some cases the action of TrAFs may be protective against disorders
that involve translocational regulation.
Selected Publications:
R.S. Hegde and V.R. Lingappa (1996). Sequence-specific alteration of the
ribosome-membrane junction exposes nascent secretory proteins to the cytosol.
Cell 85:217- 228. R.S. Hegde and V.R. Lingappa (1997). Membrane Protein
Biogenesis. Cell 91:575-582.
R. S. Hegde, J.A. Mastrianni, M. Scott, K. A. DeFea, P. Tremblay, M. Torchia,
S.J. DeArmond, S. B. Prusiner, and V. R. Lingappa (1998). Pathogenesis
of Spontaneous Neurodegenerative Disease Involves a Transmembrane Form
of the Prion Protein. Science 279:827-34.
R. S. Hegde, S. Voigt, T. A. Rapoport, and V. R. Lingappa (1998). TRAM
Regulates the Exposure of Nascent Secre-tory Proteins to the Cytosol During
Translocation into the Endoplasmic Reticulum. Cell 92:621-31.
R.S. Hegde, S.Voigt, and V.R. Lingappa (1998). Regulation of protein topology
by transacting factors at the endoplasmic reticulum. Molecular Cell in
press.
Contact Information:
Email: vrl@itsa.ucsf.edu
Phone: 415/ 476-2762
Address: Box 0444, Room HSW 712
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
|
