한빛사 논문
Ruiqiong Guoa, Zixuan Cangb, Jiaqi Yaoa, Miyeon Kima, Erin Deansc,1, Guowei Weib, Seung-gu Kangd,2, and Heedeok Honga,c,2
aDepartment of Chemistry, Michigan State University, East Lansing, MI 48824; bDepartment of Mathematics, Michigan State University, East Lansing, MI 48824; cDepartment of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824; and dComputational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598
1Present address: Graduate Program in Biochemistry and Biophysics, Brandeis University, Waltham, MA 02453.
2To whom correspondence may be addressed.
Abstract
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.
membrane protein stability, cavity, packing, GlpG, steric trapping
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