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and
*Department of Biology, University of California San Diego, La
Jolla, California 92093; and
The degradation rate of 3-hydroxy-3-methylglutaryl CoA
reductase (HMG-R), a key enzyme of the mevalonate pathway, is regulated through a feedback mechanism by the mevalonate pathway. To discover the
intrinsic determinants involved in the regulated degradation of the
yeast HMG-R isozyme Hmg2p, we replaced small regions of the Hmg2p
transmembrane domain with the corresponding regions from the other,
stable yeast HMG-R isozyme Hmg1p. When the first 26 amino acids of
Hmg2p were replaced with the same region from Hmg1p, Hmg2p was
stabilized. The stability of this mutant was not due to
mislocalization, but rather to an inability to be recognized for
degradation. When amino acid residues 27-54 of Hmg2p were replaced
with those from Hmg1p, the mutant was still degraded, but its
degradation rate was poorly regulated. The degradation of this mutant
was still dependent on the first 26 amino acid residues and on the
function of the HRD genes. These mutants showed altered
ubiquitination levels that were well correlated with their degradative
phenotypes. Neither determinant was sufficient to impart regulated
degradation to Hmg1p. These studies provide evidence that there are
sequence determinants in Hmg2p necessary for degradation and optimal
regulation, and that independent processes may be involved in Hmg2p
degradation and its regulation.
Department of Molecular and
Cellular Biology, Division of Genetics, University of California
Berkeley, Berkeley, California 94720
Present address: Department of Genetics,
Harvard Medical School, Boston MA.
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