Areas of Interest
Work in this laboratory is focused towards the understanding of
the molecular basis of the biological activities of
membrane-bound proteins. Our current work is directed at
defining the molecular components that mediate the degradation
of the stearoyl CoA desaturase (SCD). The protein components of
endoplasmic reticulum (ER) are in a constant state of renewal.
The half-life of ER proteins varies from minutes to several
days. Contrary to the well-studied ubiquitin-proteasome system
that is responsible for degradation of misfolded proteins or
proteins that result from errors in transcription or
translation, the proteolytic machinery responsible for selective
degradation of fully functional, short-lived membrane proteins
is unknown. SCD is a short-lived ER protein that is synthesized
and degraded in the ER by other than proteasome or lysosomal
proteases. SCD is the rate-limiting enzyme in the biosynthesis
of unsaturated fatty acids and plays a central role in the
regulation of lipid metabolism. We utilize a combination of
genomics and mass spectrometric approaches to identify the
proteases responsible for the specific degradation of SCD. We
expect that such studies may yield new insight in the normal
turnover of ER proteins.
Lab Rotation Projects
Project: Identification and degradation of short-lived
proteins in mammalian endoplasmic reticulum (ER) mebrane.
The degradation of short-lived membrane proteins is poorly
understood. The half-life of ER proteins is quite variable. The
mean half-life of an ER protein is approximately 2 days, but the
turnover rate of the short-lived membrane proteins is quite
rapid, less than few hours. It is generally accepted that
degradation of these proteins is localized to the ER. The
protease(s) involved and the mechanisms by which short –lived
proteins are selected and degraded in the ER are unknown. How
the short-lived proteins are distinguished from misfolded or
improperly assembled proteins remains to be determined. The
ubiquitin-proteasome pathway is believed to degrade cytosolic
proteins and is implicated in the disposal of improperly
assembled or misfolded membrane proteins, however, attempts to
implicate proteasome system in the degradation of short-lived ER
proteins has not been successful.
As a model protein for these studies, we are using the
stearoyl-CoA desaturase (SCD). SCD is an short-lived, intrinsic
membrane protein of the ER. It is the rate-limiting enzyme in
the synthesis of monounsaturated fatty acids (MUFAs). Although,
MUFAs such as oleate are readily available in mammalian diets,
for reasons unknown, dietary oleate fails to enter the
subcellular compartment where oleate is incorporated into
phospholipids and cholesterol esters.
Studies with abj/abj mice which have a natural mutation in
the SCD gene and the ablation of SCD activity, results in
decreased triglyceride, and cholesterol ester synthesis leading
to increased fatty acid oxidation,and reduced body adiposity.
Also mice lackind SCD activity display resistance towards
diet-induced obesity.
Students who whish to examine the mechanism of degradation of
SCD in the ER of hepatocytes, or other cell line membranes are
more than welcome. Projects on the SCD protease inhibitors in
hepatic ER and their effects on triglyceride and cholesterol
ester synthesis in mice or rats are also available.
Selected Publications
F.S. Heinemann and J. Ozols. 2003. Stearoyl-CoA desaturase, a
short-lived protein of endoplasmic reticulum with multiple
control mechanisms. Prostaglandins, Leukotrines and Essential
Fatty Acids 68, 123-133. Review.
F.S. Heinemann, H. Mziaut, G. Korza and J. Ozols. 2003. A
microsomal endopeptidase from liver that preferentially degrades
stearoyl-CoA desaturase. Biochemistry 42 (23), 6929-6937.
F.S. Heinemann, G. Korza and J. Ozols. 2003. A plasminogen-like
protein selectively degrades steroyl-CoA desaturase in liver
microsomes. J. Biol. Chem. 278, 42966-42975.
H. Mziaut, G. Korza and J. Ozols. 2000. The N terminus of
microsomal D9 stearoyl-CoA desaturase contains the sequence
determinant for its rapid degradation. Proc. Natl. Acad. Sci.
97, 8883-8888. |
