Vitamin K epoxide reductase and its paralogous enzyme have different structures and functions.
Vitamin K epoxide reductase and its paralogous enzyme have different structures and functions.
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DOI：
10.1038/s41598-017-18008-3
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发表时间：
2017-12-15
影响因子：
4.6
通讯作者：
Tie JK
中科院分区：
文献类型：
--
作者：
Sinhadri BCS;Jin DY;Stafford DW;Tie JK
维生素K环氧化物还原酶（VKOR）是维生素K依赖性羧化的关键酶，但其旁系同源酶VKOR-like（VKORL）的生理功能尚不清楚。虽然这两种酶共享大约50%的蛋白质序列同源性，但VKOR的膜拓扑结构仍有争议。在这里，我们探讨了这两种酶的膜拓扑结构和二硫键连接的寡聚化的差异。在有争议的跨膜（TM）区域的关键氨基酸残基突变的结果显示，第二个TM结构域中提出的4-TM模型的VKOR不作为一个真正的TM螺旋的功能;支持VKOR是一个3-TM蛋白，这是从VKORL不同。此外，改变VKORL的两个保守半胱氨酸残基之间的环序列会影响其活性，支持VKORL的保守环半胱氨酸参与其活性位点再生的观点。然而，VKOR中的类似突变并不影响其酶活性。最后，我们的研究结果表明，虽然VKOR和VKORL形成二硫键连接的寡聚体，参与寡聚化的半胱氨酸残基似乎是不同的。总体而言，VKOR和VKORL之间的结构和功能差异表明，VKORL可能具有不同的生理功能，而不是回收维生素K。
Vitamin K epoxide reductase (VKOR) is an essential enzyme for vitamin K-dependent carboxylation, while the physiological function of its paralogous enzyme VKOR-like (VKORL) is yet unknown. Although these two enzymes share approximately 50% protein sequence homology, the membrane topology of VKOR is still in debate. Here, we explored the differences in the membrane topology and disulfide-linked oligomerization of these two enzymes. Results from mutating the critical amino acid residues in the disputed transmembrane (TM) regions revealed that the second TM domain in the proposed 4-TM model of VKOR does not function as an authentic TM helix; supporting VKOR is a 3-TM protein, which is different from VKORL. Additionally, altering the loop sequence between the two conserved cysteine residues of VKORL affects its activity, supporting the notion that the conserved loop cysteines of VKORL are involved in its active site regeneration. However, a similar mutation in VKOR does not affect its enzymatic activity. Finally, our results show that although both VKOR and VKORL form disulfide-linked oligomers, the cysteine residues involved in the oligomerization appear to be different. Overall, the structural and functional differences between VKOR and VKORL shown here indicate that VKORL might have a different physiological function other than recycling vitamin K.
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