Ye J, Davé U P, Grishin N V, Goldstein J L, Brown M S
Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046, USA.
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5123-8. doi: 10.1073/pnas.97.10.5123.
The NH(2)-terminal domains of membrane-bound sterol regulatory element-binding proteins (SREBPs) are released into the cytosol by regulated intramembrane proteolysis, after which they enter the nucleus to activate genes encoding lipid biosynthetic enzymes. Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a hydrophobic zinc metalloprotease that cleaves SREBPs at a membrane-embedded leucine-cysteine bond. In the current study, we use domain-swapping methods to localize the residues within the SREBP-2 membrane-spanning segment that are required for cleavage by S2P. The studies reveal a requirement for an asparagine-proline sequence in the middle third of the transmembrane segment. We propose a model in which the asparagine-proline sequence serves as an NH(2)-terminal cap for a portion of the transmembrane alpha-helix of SREBP, allowing the remainder of the alpha-helix to unwind partially to expose the peptide bond for cleavage by S2P.
膜结合型固醇调节元件结合蛋白(SREBPs)的氨基末端结构域通过受调控的膜内蛋白水解作用释放到细胞质中,之后它们进入细胞核以激活编码脂质生物合成酶的基因。膜内蛋白水解由位点2蛋白酶(S2P)催化,S2P是一种疏水性锌金属蛋白酶,可在膜嵌入的亮氨酸 - 半胱氨酸键处切割SREBPs。在本研究中,我们使用结构域交换方法来定位SREBP - 2跨膜区段中被S2P切割所需的残基。研究揭示了跨膜区段中间三分之一处的天冬酰胺 - 脯氨酸序列的必要性。我们提出了一个模型,其中天冬酰胺 - 脯氨酸序列作为SREBP跨膜α螺旋一部分的氨基末端帽,使α螺旋的其余部分部分展开以暴露肽键供S2P切割。