气候变化领域集成服务门户(CCPortal): Structural cavities are critical to balancing stability and activity of a membrane-integral enzyme

CCPortal

DOI	10.1073/pnas.1917770117
	Structural cavities are critical to balancing stability and activity of a membrane-integral enzyme
	Guo R.; Cang Z.; Yao J.; Kim M.; Deans E.; Wei G.; Kang S.-G.; Hong H.
发表日期	2020
ISSN	0027-8424
起始页码	22146
结束页码	22156
卷号	117 期号:36
英文摘要	Packing interaction is a critical driving force in the folding of helical membrane proteins. Despite the importance, packing defects (i.e., cavities including voids, pockets, and pores) are prevalent in membrane-integral enzymes, channels, transporters, and receptors, playing essential roles in function. Then, a question arises regarding how the two competing requirements, packing for stability vs. cavities for function, are reconciled in membrane protein structures. Here, using the intramembrane protease GlpG of Escherichia coli as a model and cavity-filling mutation as a probe, we tested the impacts of native cavities on the thermodynamic stability and function of a membrane protein. We find several stabilizing mutations which induce substantial activity reduction without distorting the active site. Notably, these mutations are all mapped onto the regions of conformational flexibility and functional importance, indicating that the cavities facilitate functional movement of GlpG while compromising the stability. Experiment and molecular dynamics simulation suggest that the stabilization is induced by the coupling between enhanced protein packing and weakly unfavorable lipid desolvation, or solely by favorable lipid solvation on the cavities. Our result suggests that, stabilized by the relatively weak interactions with lipids, cavities are accommodated in membrane proteins without severe energetic cost, which, in turn, serve as a platform to fine-tune the balance between stability and flexibility for optimal activity. © 2020 National Academy of Sciences. All rights reserved.
英文关键词	Cavity; GlpG; Membrane protein stability; Packing; Steric trapping
语种	英语
scopus关键词	membrane enzyme; DNA binding protein; Escherichia coli protein; GlpG protein, E coli; membrane protein; proteinase; RHBDL2 protein, human; serine proteinase; Article; conformational transition; controlled study; enzyme activity; enzyme conformation; enzyme stability; enzyme structure; Escherichia coli; human; molecular dynamics; mutation; priority journal; protein function; solvation; thermodynamics; chemistry; enzyme active site; metabolism; molecular model; protein conformation; protein folding; protein stability; Catalytic Domain; DNA-Binding Proteins; Endopeptidases; Escherichia coli Proteins; Humans; Membrane Proteins; Models, Molecular; Molecular Dynamics Simulation; Mutation; Protein Conformation; Protein Folding; Protein Stability; Serine Endopeptidases
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/160225
作者单位	Guo, R., Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States; Cang, Z., Department of Mathematics, Michigan State University, East Lansing, MI 48824, United States; Yao, J., Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States; Kim, M., Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States; Deans, E., Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824, United States; Wei, G., Department of Mathematics, Michigan State University, East Lansing, MI 48824, United States; Kang, S.-G., Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, United States; Hong, H., Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States, Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824, United States
推荐引用方式 GB/T 7714	Guo R.,Cang Z.,Yao J.,et al. Structural cavities are critical to balancing stability and activity of a membrane-integral enzyme[J],2020,117(36).
APA	Guo R..,Cang Z..,Yao J..,Kim M..,Deans E..,...&Hong H..(2020).Structural cavities are critical to balancing stability and activity of a membrane-integral enzyme.Proceedings of the National Academy of Sciences of the United States of America,117(36).
MLA	Guo R.,et al."Structural cavities are critical to balancing stability and activity of a membrane-integral enzyme".Proceedings of the National Academy of Sciences of the United States of America 117.36(2020).