Ste24 enzymes, a family of eukaryotic integral membrane proteins, are zinc metalloproteases (ZMPs) originally characterized as "CAAX proteases" targeting prenylated substrates, including a-factor mating pheromone in yeast and prelamin A in humans. Recently, Ste24 was shown to also cleave nonprenylated substrates. Reduced activity of the human ortholog, HsSte24, is linked to multiple disease states (laminopathies), including progerias and lipid disorders. Ste24 possesses a unique "α-barrel" structure consisting of seven transmembrane (TM) α-helices encircling a large intramembranous cavity (~14 000 Å3 ). The catalytic zinc, coordinated via a HExxH…E/H motif characteristic of gluzincin ZMPs, is positioned at one of the cavity's bases. The interrelationship between Ste24 as a gluzincin, a long-studied class of soluble ZMPs, and as a novel cavity-containing integral membrane protein protease has been minimally explored to date. Informed by homology to well-characterized soluble, gluzincin ZMPs, we develop a model of Ste24 that provides a conceptual framework for this enzyme family, suitable for development and interpretation of structure/function studies. The model consists of an interfacial, zinc-containing "ZMP Core" module surrounded by a "ZMP Accessory" module, both capped by a TM helical "α-barrel" module of as yet unknown function. Multiple sequence alignment of 58 Ste24 orthologs revealed 38 absolutely conserved residues, apportioned unequally among the ZMP Core (18), ZMP Accessory (13), and α-barrel (7) modules. This Tripartite Architecture representation of Ste24 provides a unified image of this enzyme family.

中文翻译：

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真核整合膜蛋白锌金属蛋白酶Ste24的三重结构。

Ste24酶是一个真核整合膜蛋白家族，是锌金属蛋白酶（ZMP），最初被称为“ CAAX蛋白酶”，靶向异戊二烯化的底物，包括酵母中的a因子交配信息素和人中的prelaminA。最近，Ste24还显示出可裂解未异戊二烯化的底物。人类直向同源物HsSte24的活性降低与多种疾病状态（拉丁病）有关，包括早衰症和脂质疾病。Ste24具有独特的“α桶”结构，该结构由七个跨大膜内腔（〜14 000Å3）的跨膜（TM）α螺旋组成。通过格鲁辛锌ZMPs的HExxH…E / H基序特征进行协调的催化锌位于腔体的底部之一。作为一种久经研究的可溶性ZMPs的gluzincin，Ste24之间的相互关系，迄今为止，作为一种新型的含有空腔的整体膜蛋白蛋白酶的研究已经很少。通过与特性良好的可溶性gluzincin ZMPs的同源性得知，我们开发了Ste24模型，该模型为该酶家族提供了概念框架，适用于结构和功能研究的开发和解释。该模型由一个界面，含锌的“ ZMP芯”模块和一个“ ZMP附件”模块所包围，两个模块均被功能未知的TM螺旋“α-barrel”模块封盖。58个Ste24直系同源物的多序列比对显示38个绝对保守的残基，在ZMP Core（18），ZMP Accessory（13）和α-barrel（7）模块之间分配不均。Ste24的这种三方体系结构表示形式提供了该酶家族的统一图像。