A cholesterol-sensing mechanism unfolds.

Squalene monooxygenase (SM), which synthesizes a cholesterol precursor, is degraded when cholesterol levels in the endoplasmic reticulum (ER) membrane are high, but the signal for degradation was not known. In this issue of JBC, Brown and co-workers identify an N-terminal domain in SM that interconverts in a cholesterol-sensitive manner between a membrane-binding amphipathic helix and a soluble degradation-prone segment, providing the first example of a cholesterol-degron collaboration.