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Faculty
Juris Ozols
Professor of Molecular, Microbial and Structural Biology
ozols@nso2.uchc.edu
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. |
