BIOCHEMISTRY OF UBIQUITIN-CONJUGATING ENZYMES

Project: Research project

Project Details

Description

DESCRIPTION (adapted from applicant's abstract): ER-associated degradation
refers to the process whereby membrane as well as lumenal proteins in the
endoplasmic reticulum (ER) compartment are degraded by the cytosolic 26S
proteasome. Proteins that are routed into this degradative pathway include
proteins whose levels are subjected to regulated proteolysis as well as newly
synthesized proteins that entered the ER but failed either to fold properly or
to be assembled with their constituent protein partners. In several human
hereditary diseases, extensive degradation of specific allelic variants results
in the reduction or absence of such proteins in their destined compartment,
leading to deficiency in function and disease symptoms. Examples of such
allelic variants have been found with the CFTR protein in cystic fibrosis,
alpha1-antitrypsin in childhood liver disease and adult emphysema, insulin
receptor in type A insulin resistance, LDL receptor in familial
hypercholesterolemia and in myeloperoxidase deficiency.

While the role of ubiquitin-mediated proteolysis in the degradation of
ER-associated proteins is well recognized, virtually nothing is known on the
ubiquitination process of this pathway in mammalian cells. Such information is
crucial to understand how the pathway could be regulated and to evaluate the
potential of this pathway for therapeutic intervention. The principal
investigator proposes here that ER-associated degradation in mammalian cells
utilizes a similar cascade of reactions as in the yeast Saccharomyces
cerevisiae, for which the identity of several protein participants of the
ubiquitination process have been identified by genetic analysis. The goal will
be to test this hypothesis with a model substrate system that offers the
significant advantage of being amenable to biochemical analysis. To this end,
the principal investigator has identified a set of human ubiquitin-conjugating
enzymes and ubiquitin-protein ligases that are likely participants in this
pathway. He expects that the biochemical analysis will provide important
mechanistic insights and the prerequisite information for the evaluation of
this pathway for potential therapeutic intervention.
StatusFinished
Effective start/end date3/1/012/28/02

Funding

  • National Institute of General Medical Sciences: $290,647.00

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