The integral endoplasmic
reticulum (ER) protein HMG-CoA reductase is a key enzyme of the
mevalonate pathway from which sterols and other essential molecules are
produced. The degradation of the HMGR in mammals and the Hmg2p isozyme
in yeast is regulated in response to the mevalonate pathway. Drugs that
block early enzymes of the mevalonate pathway slow degradation, leading
to increased steady state levels. Little is known about the mechanisms
responsible for this regulation. Degradation is mediated by the
HRD (HMG-CoA Reductase Degradation) genes. Studies of hrd
mutants and variants of Hmg2p suggest that the HRD genes
themselves are not the targets of mevalonate pathway regulation.
Accordingly, we have developed a screen to identify mutants deficient in
regulation of Hmg2p stability. Specifically, we have screened for
mutants that are unable to stabilize Hmg2p when flux through the
mevalonate pathway is lowered. These genes are referred to as CRD
genes (pronounced 'curd') for Control of HMG-CoA Reductase Degradation.
The first mutant identified in the screen, crd1-1 responds only
marginally to mevalonate pathway manipulation. The cloned CRD1
gene appears to be a calcium transporting ATPase and is identical to
SPF1 . We are currently evaluating the crd1 mutants in more
detail, in order to understand the role of this transporter in the
normal regulated degradation of Hmg2p.
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