胰脂肪酶及相关蛋白的底物选择性的结构基础

Frédéric Carrière , Chrislaine Withers-Martinez , Herman van Tilbeurgh , Alain Roussel , Christian Cambillau , Robert Verger
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引用次数: 130

摘要

经典的人胰脂肪酶(HPL)、豚鼠胰脂肪酶相关蛋白2 (GPLRP2)和大黄蜂毒液磷脂酶A1 (DolmI PLA1)说明了胰脂肪酶基因家族在不同底物选择性方面的分子进化过程中的三个有趣步骤。基于已知的HPL和GPLRP2嵌合体的三维结构,以及DolmI PLA1的建模,我们回顾了这三种酶的结构特征和动力学性质,以便更好地了解它们的结构-功能关系。HPL仅对甘油三酯具有显著活性,而GPLRP2具有较高的磷脂酶和半乳糖酶活性,以及相当的脂肪酶活性。GPLRP2除了由5个氨基酸残基组成的lid结构域(mini-lid)而不是HPL中的23个氨基酸残基外,与HPL具有高度的结构同源性。GPLRP2中盖子结构域的缺失允许自由进入活性位点,并减少对大底物(如半乳糖脂类)的位阻。通过定点诱变和HPL和GPLRP2盖子结构域的替代,研究了盖子结构域在底物选择性中的作用。在GPLRP2中添加大尺寸的盖子结构域,通过抑制磷脂酶活性提高了甘油三酯的底物选择性。然而,在具有GPLRP2迷你盖子的HPL突变体中,磷脂酶活性没有被诱导。因此,全长盖子结构域的存在并不是解释HPL缺乏磷脂酶活性的唯一结构特征。GPLRP2嵌合体和DolmI PLA1模型的3D结构显示,与HPL中的同源环相比,活性位点周围的表面环(β5环、β9环、盖子结构域)具有更高的亲水/亲脂平衡(HLB)。这一观察结果为GPLRP2和DolmI PLA1水解极性脂质(如磷脂)的能力提供了一种潜在的解释。综上所述,β5环、β9环和lid结构域在对甘油三酯、磷脂和半乳糖脂的底物选择性中起重要作用。
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Structural basis for the substrate selectivity of pancreatic lipases and some related proteins

The classical human pancreatic lipase (HPL), the guinea pig pancreatic lipase-related protein 2 (GPLRP2) and the phospholipase A1 from hornet venom (DolmI PLA1) illustrate three interesting steps in the molecular evolution of the pancreatic lipase gene family towards different substrate selectivities. Based on the known 3D structures of HPL and a GPLRP2 chimera, as well as the modeling of DolmI PLA1, we review here the structural features and the kinetic properties of these three enzymes for a better understanding of their structure–function relationships. HPL displays significant activity only on triglycerides, whereas GPLRP2 displays high phospholipase and galactolipase activities, together with a comparable lipase activity. GPLRP2 shows high structural homology with HPL with the exception of the lid domain which is made of five amino acid residues (mini-lid) instead of 23 in HPL. The lid domain deletion in GPLRP2 allows the free access to the active site and reduces the steric hindrance towards large substrates, such as galactolipids. The role of the lid domain in substrate selectivity has been investigated by site-directed mutagenesis and the substitution of HPL and GPLRP2 lid domains. The addition of a large-size lid domain in GPLRP2 increases the substrate selectivity for triglycerides by depressing the phospholipase activity. The phospholipase activity is, however, not induced in the case of the HPL mutant with GPLRP2 mini-lid. Therefore, the presence of a full-length lid domain is not the unique structural feature explaining the absence of phospholipase activity in HPL. The 3D structure of the GPLRP2 chimera and the model of DolmI PLA1 reveal a higher hydrophilic/lipophilic balance (HLB) of the surface loops (β5 loop, β9 loop, lid domain) surrounding the active site, as compared to the homologous loops in HPL. This observation provides a potential explanation for the ability of GPLRP2 and DolmI PLA1 to hydrolyze polar lipids, such as phospholipids. In conclusion, the β5 loop, the β9 loop, and the lid domain play an essential role in substrate selectivity towards triglycerides, phospholipids and galactolipids.

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