RELATED MEMBRANE DOMAINS IN PROTEINS OF STEROL SENSING AND CELL SIGNALING PROVIDE A GLIMPSE OF TREASURES STILL BURIED WITHIN THE DYNAMIC REALM OF INTRACELLULAR METABOLIC-REGULATION

Recent discoveries in the regulation of cholesterol metabolism have do cumented a two step proteolytic pathway that regulates nuclear targeti ng of the sterol regulatory element binding proteins. Sterol regulator y element binding protein cleavage activating protein is a newly ident ified protein that modulates the proteolytic maturation of the sterol regulatory element binding proteins. It contains a domain that is quit e similar in sequence to the membrane spanning region of the rate cont rolling enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase. The membrane domain of the reductase is involve d in its post-translational regulation by cholesterol. The molecular d efect in the intracellular cholesterol storage disease, Niemann-Pick t ype C, has also recently been identified. Surprisingly, the affected g ene encodes a protein with similarity to the membrane domains that are conserved in 3-hydroxy-3-methylglutaryl reductase and sterol regulato ry element binding protein cleavage activating protein. Furthermore, t he cell surface receptor for the sterol modified hedgehog morphogen, P atched, also contains a membrane domain with significant similarity to this putative sterol monitoring domain. These recent developments sug gest a common mechanism for sensing intracellular sterol levels and ce ll signaling, which is based on the function of related membrane domai ns that are contained in key regulatory proteins. (C) 1998 Rapid Scien ce Ltd.