Department of Biochemistry, Faculty of Medicine & Dentistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7.
Department of Biochemistry, Faculty of Medicine & Dentistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7.
J Mol Biol. 2020 Aug 21;432(18):5052-5062. doi: 10.1016/j.jmb.2020.04.006. Epub 2020 Apr 19.
Intramembrane proteolysis, although once a controversial concept, is a widely studied field. Four classes of intramembrane proteases have been identified and are classified by their catalytic mechanism of peptide bond hydrolysis: metallo, glutamyl, aspartyl, and serine proteases. One of the most studied of these classes is the rhomboid superfamily of serine intramembrane proteases. Rhomboids consist of six or seven transmembrane segments that form a helical bundle within the membrane and are involved in a multitude of cellular processes. These proteases are characterized by a catalytic dyad composed of a serine and a histidine residue, which distinguishes them from classical serine proteases wherein a catalytic triad is utilized. Of all currently identified rhomboid proteases, one that is of great interest is the mammalian mitochondrial rhomboid protease PARL. Most well known for its processing of the kinase PINK1 and potential link to Parkinson's disease, PARL has been shown to cleave a variety of substrates within the cell including PGAM5, Smac, TTC19, and others. While recent proteomic studies have provided insight on new potential substrates of PARL, its regulation, activity, and role in maintaining mitochondrial homeostasis remain largely unknown.
尽管跨膜蛋白水解曾经是一个有争议的概念，但它是一个广泛研究的领域。已经确定了四类跨膜蛋白酶，并根据其肽键水解的催化机制进行分类：金属蛋白酶、谷氨酰蛋白酶、天冬氨酸蛋白酶和丝氨酸蛋白酶。其中研究最多的一类是丝氨酸跨膜蛋白酶的菱形超家族。菱形蛋白酶由六个或七个跨膜片段组成，在膜内形成一个螺旋束，并参与多种细胞过程。这些蛋白酶的特征是由一个丝氨酸和一个组氨酸残基组成的催化二联体，这将它们与经典的丝氨酸蛋白酶区分开来，经典的丝氨酸蛋白酶使用催化三联体。在所有目前鉴定的菱形蛋白酶中，哺乳动物线粒体菱形蛋白酶 PARL 是非常引人注目的一种。PARL 最著名的是其对激酶 PINK1 的加工，以及与帕金森病的潜在联系，已证明它可以在细胞内切割多种底物，包括 PGAM5、Smac、TTC19 等。虽然最近的蛋白质组学研究提供了对 PARL 的新潜在底物的深入了解，但它的调节、活性及其在维持线粒体动态平衡中的作用在很大程度上仍是未知的。
