Jn. Athanikar et Tf. Osborne, SPECIFICITY IN CHOLESTEROL REGULATION OF GENE-EXPRESSION BY COEVOLUTION OF STEROL REGULATORY DNA ELEMENT AND ITS BINDING-PROTEIN, Proceedings of the National Academy of Sciences of the United Statesof America, 95(9), 1998, pp. 4935-4940
When demand for cholesterol rises in mammalian cells, the sterol regul
atory element (SRE) binding proteins (SREBPs) are released from their
membrane anchor through proteolysis. Then, the N-terminal region enter
s the nucleus and activates genes of cholesterol uptake and biosynthes
is. Basic helix-loop-helix (bHLH) proteins such as SREBPs bind to a pa
lindromic DNA sequence called the E-box (5'-CANNTG-3'). However, SREBP
s are special because they also bind direct repeat elements called SRE
s, Importantly, sterol regulation of all promoters studied thus far is
mediated by SREBP binding only to SREs, To study the reason for this
we converted the direct repeat SRE from the sterol-regulated low-densi
ty lipoprotein receptor promoter into an E-box, In this report we show
that SREBPs are still able to bind and activate this promoter however
, sterol regulation is lost. The results are consistent with the mutan
t promoter being a target for prormiscuous activation by constitutivel
y expressed E-box binding bHLH proteins that are not regulated by chol
esterol. Kim and coworkers [Kim, J. B., Spotts, G. D., Halvorsen, Y.-D
., Shih, H.-M., Ellenberger, T,, Towle, H, C, & Spiegelman, B, M, (199
5) Mel. Cell. Biol, 15, 2582-2588] demonstrated that the dual DNA bind
ing specificity of SREBPs is caused by a specific tyrosine in the cons
erved basic region of the DNA binding domain that corresponds to an ar
ginine in all other bHLH proteins that recognize only E-boxes, Taken t
ogether the data suggest an evolutionary mechanism where a DNA binding
protein along with its recognition site have coevolved to ensure maxi
mal specificity and sensitivity in a crucial nutritional regulatory re
sponse.