膜蛋白Presenilin 1的跨膜结构及催化机制

Transmembrane Structure and Catalytic Mechanism of Presenilin 1

膜蛋白presenilin1(PS1)是γ分泌酶的催化组分,是催化产生β淀粉样蛋白(β-amyloid,Aβ)的关键蛋白酶,因此也是治疗阿尔茨海默病(Alzheimer’s disease,AD)的主要靶点.PS1属于膜内裂解蛋白酶家族,这是一类在膜脂双层内部催化肽键水解断裂的蛋白酶.PS1其独特的跨膜结构和催化机制虽然还未完全揭示,但近期相关的研究取得了重要成果:PS1有10个疏水区,跨膜9次,其N端位于胞内,C端位于胞膜外或者内质网腔内,亦或不同程度地插入膜内,2个起催化作用的天冬氨酸残基都位于疏水性的膜内,膜蛋白底物被催化水解时必须先结合到酶的疏水表面上来,然后再进入位于活性部位.虽然PS1的晶体从未获得,但2006年首次解析的膜内裂解蛋白酶GlpG的晶体结构和所提出的催化机理为PS1催化机理的揭示奠定了基础,也为设计和筛选PS1/γ分泌酶的特异性抑制剂提供了理论依据.

Integral membrane protein presenilin 1 （PS1） represents the catalytic component of γ-secretase, and is the crucial protease in the production of β-amyloid （Aβ）. Therefore, it is believed the pharmacological target for Alzheimer＇s disease. Presenilin 1 belongs to the family of intramembrane-cleaving protease, a kind of proteases that catalyse peptide bond hydrolysis within lipid bilayer membranes, although its unique transmembrane structure and catalytic mechanism are not revealed completely, the current important development have been achieved, PS1 has ten hydrophobic regions, which form nine transmembrane （TM） domains, the N terminus is in the cytosol, whereas the C terminus either localizes to the lumen/extracellular space or embeds in the membrane bilayer, two catalytic aspartates lie in the hydrophobic membrane bilayer, and the membrane protein substrate first must contact the hydrophobic outer surface of the protease before its entry into the active site. Although the crystal structure of presenilin 1 has not yet been determined, the significant achievement in the research of first crystal structure of intramembrane-cleaving protease, GlpG, and the implications for the mechanism of intramembrane proteolysis lay the foundation for revealing the catalytic mechanism of presenilin 1, and will provide scientific theoretical bases for the design and selection of substrate-specific inhibitors of presenilin 1 or γ-secretase.