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Cavin3 interacts with cavin1 and caveolin1 to increase surface dynamics of caveolae
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). (Richard Lundmark)
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). (Richard Lundmark)
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). (Richard Lundmark)
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). (Richard Lundmark)
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2015 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 128, no 5, 979-991 p.Article in journal (Refereed) Published
Abstract [en]

Caveolae are invaginations of the cell surface thought to regulate membrane tension, signalling, adhesion and lipid homeostasis due to their dynamic behaviour ranging from stable surface association to dynamic rounds of fission and fusion with the plasma membrane. The caveolae coat is generated by oligomerisation of the membrane protein caveolin and the family of cavin proteins. Here, we show that cavin3 is targeted to caveolae by cavin1 where it interacts with the scaffolding domain of caveolin1 and promote caveolae dynamics. We found that the N-terminal region of cavin3 binds a trimer of the cavin1 N-terminus in competition with a homologous cavin2 region, showing that the cavins form distinct subcomplexes via their N-terminal regions. Our data shows that cavin3 is enriched at deeply invaginated caveolae and that loss of cavin3 in cells results in an increase of stable caveolae and a decrease of caveolae with short duration time at the membrane. We propose that cavin3 is recruited to the caveolae coat by cavin1 to interact with caveolin1 and regulate the duration time of caveolae at the plasma membrane.

Place, publisher, year, edition, pages
2015. Vol. 128, no 5, 979-991 p.
Keyword [en]
Cavin1, Cavin3, Caveolin1, Caveolae, EHD2
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-92497DOI: 10.1242/jcs.161463ISI: 000350569900014OAI: oai:DiVA.org:umu-92497DiVA: diva2:741056
Available from: 2014-08-27 Created: 2014-08-27 Last updated: 2017-12-05Bibliographically 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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1668
Keyword
Caveolae, caveolin, EHD2, cavin, microdomain, microscopy, TIRF, AFM
National Category
Cell and Molecular Biology
Research subject
Medical Biochemistry
Identifiers
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)
Opponent
Supervisors
Available from: 2014-08-29 Created: 2014-08-27 Last updated: 2018-01-11Bibliographically approved
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Mohan, JaganMorén, BjörnLarsson, ElinHolst, MikkelLundmark, Richard
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Department of Medical Biochemistry and BiophysicsMolecular Infection Medicine Sweden (MIMS)Department of Integrative Medical Biology (IMB)
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