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

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Item Type:Article
Title:Structural insights into the activation mechanism of dynamin-like EHD ATPases
Creators Name:Melo, A.A. and Hegde, B.G. and Shah, C. and Larsson, E. and Isas, J.M. and Kunz, S. and Lundmark, R. and Langen, R. and Daumke, O.
Abstract: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.
Keywords:Dynamin Superfamily, Endocytic Pathways, Protein Structure, Membrane Remodeling, Autoinhibition
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:5629-5634
Date:30 May 2017
Official Publication:https://doi.org/10.1073/pnas.1614075114
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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