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EHD2 regulates caveolar dynamics via ATP-driven targeting and oligomerization
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2012 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 7, 1316-1329 p.Article in journal (Refereed) Published
Abstract [en]

Eps15 homology domain-containing 2 (EHD2) belongs to the EHD-containing protein family of dynamin-related ATPases involved in membrane remodeling in the endosomal system. EHD2 dimers oligomerize into rings on highly curved membranes, resulting in stimulation of the intrinsic ATPase activity. In this paper, we report that EHD2 is specifically and stably associated with caveolae at the plasma membrane and not involved in clathrin-mediated endocytosis or endosomal recycling, as previously suggested. EHD2 interacts with pacsin2 and cavin1, and ordered membrane assembly of EHD2 is dependent on cavin1 and caveolar integrity. While the EHD of EHD2 is dispensable for targeting, we identified a loop in the nucleotide-binding domain that, together with ATP binding, is required for caveolar localization. EHD2 was not essential for the formation or shaping of caveolae, but high levels of EHD2 caused distortion and loss of endogenous caveolae. Assembly of EHD2 stabilized and constrained caveolae to the plasma membrane to control turnover, and depletion of EHD2, resulting in endocytic and more dynamic and short-lived caveolae. Thus, following the identification of caveolin and cavins, EHD2 constitutes a third structural component of caveolae involved in controlling the stability and turnover of this organelle.

Place, publisher, year, edition, pages
American society for cell biology , 2012. Vol. 23, no 7, 1316-1329 p.
National Category
Cell and Molecular Biology
URN: urn:nbn:se:umu:diva-55359DOI: 10.1091/mbc.E11-09-0787ISI: 000302215400016OAI: diva2:529875
Available from: 2012-05-31 Created: 2012-05-14 Last updated: 2014-09-08Bibliographically approved
In thesis
1. Caveolae associated proteins and how they effect caveolae dynamics
Open this publication in new window or tab >>Caveolae associated proteins and how they effect caveolae dynamics
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Caveolae-associerade proteiner och hur dom påverkar dynamiken hos caveolae
Abstract [en]

Caveolae are a type of invaginated membrane domain that has been shown to be involved in several disease states, including lipodystrophy, muscular dystrophies and cancer. Several of these diseases are caused by the lack of caveolae or caveolae-related signaling deficiencies in the tissues in which the caveolar domain are abundant such as lung, adipose, muscle and their related endothelial cells. Caveolae are formed through the assembly of the membrane inserted protein caveolin, cholesterol and the recently described family of cavin proteins, which together form the caveolae coat. The work in this thesis focuses on understanding the protein components and mechanisms that control the biogenesis and dynamics of caveolae.

We have found that the protein EHD2 is an important regulator and stabilizer of the caveolar domain at the cell membrane. EHD2 is a dimeric ATPase known to oligomerize into ring-like structures around lipid membranes to control their shape. We have characterized the domain interactions involved in the specific targeting and assembly of this protein at caveolae. We propose a stringent regulatory mechanism for the assembly of EHD2 involving ATP binding and switching of the EH domain position to release the N-terminus and facilitate oligomerization in the presence of membrane species. We show that loss of EHD2 in cells results in hyper- dynamic caveolae and that caveolae stability at the membrane can be restored by reintroducing EHD2 into these cells.

In a study of the protein cavin-3, which is known to be an integral component of the caveolar coat, we showed that this protein is targeted to caveolae via direct binding to the caveolar core protein caveolin1. Furthermore, we show that cavin-3 is enriched at deeply invaginated caveolae and regulate the duration time of caveolae at the cell surface.

In combination with a biochemical and cellbiological approach, the advanced fluorescence microscopy techniques, like Fluorescence Recovery After Photobleaching (FRAP), Total Internal Reflection microscopy (TIRF), combined with correlative Atomic Force Microscopy (AFM) have allowed us to characterize distinct caveolae-associated proteins and their respective functions at caveolae.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2014. 54 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1668
Caveolae, caveolin, EHD2, cavin, microdomain, microscopy, TIRF, AFM
National Category
Cell and Molecular Biology
Research subject
Medical Biochemistry
urn:nbn:se:umu:diva-92500 (URN)978-91-7601-114-0 (ISBN)
Public defence
2014-09-19, N420, Naturvetarhuset, Umeå Universitet, Umeå, 10:00 (English)
Available from: 2014-08-29 Created: 2014-08-27 Last updated: 2014-08-29Bibliographically approved

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