Structural insights into the activation mechanism of dynamin-like EHD ATPases

Eps15 (epidermal growth factor receptor pathway substrate 15)-homology domain containing proteins (EHDs) comprise a family of dynamin-related mechano-chemical ATPases involved in cellular membrane trafficking. Previous studies have revealed the structure of the EHD2 dimer, but the molecular mechanis...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-05, Vol.114 (22), p.5629-5634
Main Authors: Melo, Arthur Alves, Hegde, Balachandra G., Shah, Claudio, Larsson, Elin, Isas, J. Mario, Kunz, Séverine, Lundmark, Richard, Langen, Ralf, Daumke, Oliver
Format: Article
Language:English
Subjects:
Activation
Adenosine triphosphatase
autoinhibition
Biological Sciences
Cellular structure
Conformation
Crystal structure
Dynamin
dynamin superfamily
Electron spin
endocytic pathways
Epidermal growth factor
Guanosine triphosphatases
Homology
Membrane proteins
membrane remodeling
Membrane trafficking
Membranes
Molecular modelling
Molecular structure
Molecules
Physical Sciences
protein structure
Proteins
Recruitment
Spin resonance
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Summary:Eps15 (epidermal growth factor receptor pathway substrate 15)-homology domain containing proteins (EHDs) comprise a family of dynamin-related mechano-chemical ATPases involved in cellular membrane trafficking. Previous studies have revealed the structure of the EHD2 dimer, but the molecular mechanisms of membrane recruitment and assembly have remained obscure. Here, we determined the crystal structure of an amino-terminally truncated EHD4 dimer. Compared with the EHD2 structure, the helical domains are 50° rotated relative to the GTPase domain. Using electron paramagnetic spin resonance (EPR), we show that this rotation aligns the two membrane- binding regions in the helical domain toward the lipid bilayer, allowing membrane interaction. A loop rearrangement in GTPase domain creates a new interface for oligomer formation. Our results suggest that the EHD4 structure represents the active EHD conformation, whereas the EHD2 structure is autoinhibited, and reveal a complex series of domain rearrangements accompanying activation. A comparison with other peripheral membrane proteins elucidates common and specific features of this activation mechanism.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1614075114