The crystal structure of the rhomboid peptidase from Haemophilus influenzae provides insight into intramembrane proteolysis
The crystal structure of the rhomboid peptidase from Haemophilus influenzae provides insight into intramembrane proteolysis
复制标题
DOI：
10.1073/pnas.0609981104
复制
发表时间：
2007-01-16
影响因子：
11.1
通讯作者：
James, Michael N. G.
中科院分区：
文献类型：
--
作者：
Lemieux, M. Joanne;Fischer, Sarah J.;James, Michael N. G.
菱形肽酶是调节膜内肽酶家族的成员，其切割整合膜蛋白的跨膜区段。菱形肽酶在果蝇的发育过程和酵母的线粒体维持中起重要作用。最近，菱形肽酶的功能已直接与细胞凋亡。我们已经解决了菱形肽酶从流感嗜血杆菌（hiGlpG）的结构到2.2埃分辨率。通过使用大肠杆菌菱形（ecGipG）的坐标，主要通过分子置换来提供对hiGipG晶体的定相。这些菱形肽酶的结构结果使我们能够推测在膜环境中底物裂解的催化机制。我们已经确定了亲核丝氨酸的保守组氨酸的一般碱/酸功能的相对处置。在菱形结构的上下文中建模四肽底物揭示了含氧阴离子孔，其包含第二保守组氨酸的侧链和亲核丝氨酸残基的主链NH。在hiGlpG和ecGlpG结构中，水分子占据该氧阴离子空穴。
Rhomboid peptidases are members of a family of regulated intramembrane peptidases that cleave the transmembrane segments of integral membrane proteins. Rhomboid peptidases have been shown to play a major role in developmental processes in Drosophila and in mitochondrial maintenance in yeast. Most recently, the function of rhomboid peptidases has been directly linked to apoptosis. We have solved the structure of the rhomboid peptidase from Haemophilus influenzae (hiGIpG) to 2.2-angstrom resolution. The phasing for the crystals of hiGIpG was provided mainly by molecular replacement, by using the coordinates of the Escherichia coli rhomboid (ecGIpG). The structural results on these rhomboid peptidases have allowed us to speculate on the catalytic mechanism of substrate cleavage in a membranous environment. We have identified the relative disposition of the nucleophilic serine to the general base/acid function of the conserved histidine. Modeling a tetrapeptide substrate in the context of the rhomboid structure reveals an oxyanion hole comprising the side chain of a second conserved histidine and the main-chain NH of the nucleophilic serine residue. In both hiGIpG and ecGIpG structures, a water molecule occupies this oxyanion hole.