The endoplasmic reticulum (ER) quality control pathway destroys misfolded and unassembled proteins in the ER. Most substrates of this ER-associated degradation (ERAD) pathway are constitutively targeted for destruction through recognition of poorly understood structural hallmarks of misfolding. However, the normal @entity375 ER membrane protein @entity2453 reductase ( @entity58175 ) undergoes ERAD that is physiologically regulated by @entity5068 pathway signals. We have proposed that @entity58175 ERAD occurs by a regulated transition to an ERAD quality control substrate. Consistent with this, we had previously shown that @entity58175 is strongly stabilized by chemical chaperones such as @entity653 , which stabilize misfolded proteins. To understand the features of @entity58175 that permit regulated ERAD, we have thoroughly characterized the effects of chemical chaperones on @entity58175 . These agents caused a reversible, immediate, direct change in @entity58175 degradation consistent with an effect on @entity58175 structure. We devised an in vitro limited proteolysis assay of @entity58175 in its native membranes. In vitro, chemical chaperones caused a dramatic, rapid change in @entity58175 structure to a less accessible form. As in the living cell, the in vitro action of chemical chaperones was highly specific for @entity58175 and completely reversible. To evaluate the physiological relevance of this model behavior, we used the limited proteolysis assay to examine the effects of changing in vivo degradation signals on @entity58175 structure. We found that changes similar to those observed with chemical chaperones were brought about by alteration of natural degradation signal. Thus, @entity58175 can undergo significant, reversible structural changes that are relevant to the physiological control of @entity58175 ERAD. These findings support the idea that @entity58175 regulation is brought about by regulated alteration of folding state. Considering the ubiquitous nature of quality control pathways in biology, it may be that this strategy of regulation is widespread.

Structural control of endoplasmic reticulum-associated degradation: effect of chemical chaperones on XXXX reductase.

@entity5068 :: ('CHEBI:15889', 'Chemical') :: ['sterol'] @entity653 :: ('MESH:D005990', 'Chemical') :: ['glycerol'] @entity2453 :: ('MESH:C008047', 'Chemical') :: ['3-hydroxy-3-methylglutaryl-CoA'] @entity58175 :: ('851171(Tax:4932)', 'Gene') :: ['Hmg2p'] @entity375 :: ('4932', 'Species') :: ['yeast']
@entity2453 :: (MESH:C008047,Chemical) :: ['3-hydroxy-3-methylglutaryl-CoA']
