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Structural Basis for the Interaction between the Ezrin FERM-Domain and Human Aquaporins

Strandberg, Helin LU ; Hagströmer, Carl Johan LU orcid ; Werin, Balder LU ; Wendler, Markus LU orcid ; Johanson, Urban LU orcid and Törnroth-Horsefield, Susanna LU (2024) In International Journal of Molecular Sciences 25(14).
Abstract
The Ezrin/Radixin/Moesin (ERM) family of proteins act as cross-linkers between the plasma membrane and the actin cytoskeleton. This mechanism plays an essential role in processes related to membrane remodeling and organization, such as cell polarization, morphogenesis and adhesion, as well as in membrane protein trafficking and signaling pathways. For several human aquaporin (AQP) isoforms, an interaction between the ezrin band Four-point-one, Ezrin, Radixin, Moesin (FERM)-domain and the AQP C-terminus has been demonstrated, and this is believed to be important for AQP localization in the plasma membrane. Here, we investigate the structural basis for the interaction between ezrin and two human AQPs: AQP2 and AQP5. Using microscale... (More)
The Ezrin/Radixin/Moesin (ERM) family of proteins act as cross-linkers between the plasma membrane and the actin cytoskeleton. This mechanism plays an essential role in processes related to membrane remodeling and organization, such as cell polarization, morphogenesis and adhesion, as well as in membrane protein trafficking and signaling pathways. For several human aquaporin (AQP) isoforms, an interaction between the ezrin band Four-point-one, Ezrin, Radixin, Moesin (FERM)-domain and the AQP C-terminus has been demonstrated, and this is believed to be important for AQP localization in the plasma membrane. Here, we investigate the structural basis for the interaction between ezrin and two human AQPs: AQP2 and AQP5. Using microscale thermophoresis, we show that full-length AQP2 and AQP5 as well as peptides corresponding to their C-termini interact with the ezrin FERM-domain with affinities in the low micromolar range. Modelling of the AQP2 and AQP5 FERM complexes using ColabFold reveals a common mode of binding in which the proximal and distal parts of the AQP C-termini bind simultaneously to distinct binding sites of FERM. While the interaction at each site closely resembles other FERM-complexes, the concurrent interaction with both sites has only been observed in the complex between moesin and its C-terminus which causes auto-inhibition. The proposed interaction between AQP2/AQP5 and FERM thus represents a novel binding mode for extrinsic ERM-interacting partners. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
International Journal of Molecular Sciences
volume
25
issue
14
article number
7672
pages
15 pages
publisher
MDPI AG
ISSN
1422-0067
DOI
10.3390/ijms25147672
language
English
LU publication?
yes
id
d476abe5-1924-47f5-a15b-5ea887381afc
date added to LUP
2024-07-15 13:13:33
date last changed
2024-08-08 11:29:07
@article{d476abe5-1924-47f5-a15b-5ea887381afc,
  abstract     = {{The Ezrin/Radixin/Moesin (ERM) family of proteins act as cross-linkers between the plasma membrane and the actin cytoskeleton. This mechanism plays an essential role in processes related to membrane remodeling and organization, such as cell polarization, morphogenesis and adhesion, as well as in membrane protein trafficking and signaling pathways. For several human aquaporin (AQP) isoforms, an interaction between the ezrin band Four-point-one, Ezrin, Radixin, Moesin (FERM)-domain and the AQP C-terminus has been demonstrated, and this is believed to be important for AQP localization in the plasma membrane. Here, we investigate the structural basis for the interaction between ezrin and two human AQPs: AQP2 and AQP5. Using microscale thermophoresis, we show that full-length AQP2 and AQP5 as well as peptides corresponding to their C-termini interact with the ezrin FERM-domain with affinities in the low micromolar range. Modelling of the AQP2 and AQP5 FERM complexes using ColabFold reveals a common mode of binding in which the proximal and distal parts of the AQP C-termini bind simultaneously to distinct binding sites of FERM. While the interaction at each site closely resembles other FERM-complexes, the concurrent interaction with both sites has only been observed in the complex between moesin and its C-terminus which causes auto-inhibition. The proposed interaction between AQP2/AQP5 and FERM thus represents a novel binding mode for extrinsic ERM-interacting partners.}},
  author       = {{Strandberg, Helin and Hagströmer, Carl Johan and Werin, Balder and Wendler, Markus and Johanson, Urban and Törnroth-Horsefield, Susanna}},
  issn         = {{1422-0067}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{14}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Structural Basis for the Interaction between the Ezrin FERM-Domain and Human Aquaporins}},
  url          = {{http://dx.doi.org/10.3390/ijms25147672}},
  doi          = {{10.3390/ijms25147672}},
  volume       = {{25}},
  year         = {{2024}},
}