TY - JOUR
T1 - Rhomboid distorts lipids to break the viscosity-imposed speed limit of membrane diffusion
AU - Kreutzberger, Alex J.B.
AU - Ji, Ming
AU - Aaron, Jesse
AU - Mihaljević, Ljubica
AU - Urban, Siniša
N1 - Funding Information:
We are grateful to L. Lavis for generously providing fluorophores; S. Khuon and T.-L. Chew at the Advanced Imaging Center (AIC); our JHU colleagues B. Lambrus, T. Moyer, A. Paix, J. Nathans, R. Baker, and Gautam Prabhu; and C. Weaver and J. Gibas (Olympus) for help and advice. This work was supported, in part, by NIH grant R01AI066025 and an Innovator Award from Johns Hopkins University (both to S.U.). HHMI and the Packard Foundation funded our EPR spectrometer, differential scanning calorimetry calorimeter, Langmuir-Blodgett trough, and single-molecule TIRF microscope purchases. Some of the live-cell imaging data was collected at the AIC, which is supported by the Moore Foundation and HHMI’s Janelia Research Campus. S.U. is also grateful to the Visiting Scientist program of Janelia Research Campus.
Publisher Copyright:
© 2017 The Authors.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - Enzymes that cut proteins inside membranes regulate diverse cellular events, including cell signaling, homeostasis, and host-pathogen interactions. Adaptations that enable catalysis in this exceptional environment are poorly understood. We visualized single molecules of multiple rhomboid intramembrane proteases and unrelated proteins in living cells (human and Drosophila) and planar lipid bilayers. Notably, only rhomboid proteins were able to diffuse above the Saffman-Delbrück viscosity limit of the membrane. Hydrophobic mismatch with the irregularly shaped rhomboid fold distorted surrounding lipids and propelled rhomboid diffusion. The rate of substrate processing in living cells scaled with rhomboid diffusivity. Thus, intramembrane proteolysis is naturally diffusion-limited, but cells mitigate this constraint by using the rhomboid fold to overcome the “speed limit” of membrane diffusion.
AB - Enzymes that cut proteins inside membranes regulate diverse cellular events, including cell signaling, homeostasis, and host-pathogen interactions. Adaptations that enable catalysis in this exceptional environment are poorly understood. We visualized single molecules of multiple rhomboid intramembrane proteases and unrelated proteins in living cells (human and Drosophila) and planar lipid bilayers. Notably, only rhomboid proteins were able to diffuse above the Saffman-Delbrück viscosity limit of the membrane. Hydrophobic mismatch with the irregularly shaped rhomboid fold distorted surrounding lipids and propelled rhomboid diffusion. The rate of substrate processing in living cells scaled with rhomboid diffusivity. Thus, intramembrane proteolysis is naturally diffusion-limited, but cells mitigate this constraint by using the rhomboid fold to overcome the “speed limit” of membrane diffusion.
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U2 - 10.1126/science.aao0076
DO - 10.1126/science.aao0076
M3 - Article
C2 - 30705155
AN - SCOPUS:85060807301
VL - 363
JO - Science
JF - Science
SN - 0036-8075
IS - 6426
M1 - eaao0076
ER -