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2015 ; 290
(46
): 27533-44
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The Regulatory Domain of Squalene Monooxygenase Contains a Re-entrant Loop and
Senses Cholesterol via a Conformational Change
#MMPMID26434806
Howe V
; Chua NK
; Stevenson J
; Brown AJ
J Biol Chem
2015[Nov]; 290
(46
): 27533-44
PMID26434806
show ga
Squalene monooxygenase (SM) is an important control point in cholesterol
synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase. Although it is known
to associate with the endoplasmic reticulum, its topology has not been
determined. We have elucidated the membrane topology of the sterol-responsive
domain of SM comprising the first 100 amino acids fused to GFP (SM N100-GFP) by
determining the accessibility of 16 introduced cysteines to the
cysteine-reactive, membrane-impermeable reagent PEG-maleimide. We have identified
a region integrally associated with the endoplasmic reticulum membrane that is
likely to interact with cholesterol or respond to cholesterol-induced membrane
effects. By comparing cysteine accessibility with and without cholesterol
treatment, we further present evidence to suggest that cholesterol induces a
conformational change in SM N100-GFP. This change is likely to lead to its
targeted degradation by the ubiquitin-proteasome system because degradation is
blunted by treatment with the chemical chaperone glycerol, which retains SM
N100-GFP in its native conformation. Furthermore, degradation can be disrupted by
insertion of two N-terminal myc tags, implicating the N terminus in this process.
Together, this information provides new molecular insights into the regulation of
this critical control point in cholesterol synthesis.
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