Architecture of the human erythrocyte ankyrin-1 complex

Vallese, Francesca; Kim, Kookjoo; Yen, Laura Y.; Johnston, Jake; Noble, Alex J.; Calì, Tito; Clarke, Oliver B

doi:10.1038/s41594-022-00792-w

Cited by 53 publications

(53 citation statements)

References 82 publications

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“…We have previously demonstrated that there is a flexible linker between CD and TMD in the AE1 monomer that may play a significant role in the red blood cell elasticity, providing a mechanism to connect the cytoskeleton (given that AE1 CD binds various cytoplasmic proteins) with the red blood cell membrane 8 . This hypothesis is supported by the near atomic resolution data obtained in this study showing large changes in the position of the CD relative to the TMD and the recent characterization of AE1 complexes with ankyrin and protein 4.2 by cryoEM 38 , 39 .…”

Section: Resultssupporting

confidence: 84%

CryoEM structures of anion exchanger 1 capture multiple states of inward- and outward-facing conformations

et al. 2022

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Anion exchanger 1 (AE1, band 3) is a major membrane protein of red blood cells and plays a key role in acid-base homeostasis, urine acidification, red blood cell shape regulation, and removal of carbon dioxide during respiration. Though structures of the transmembrane domain (TMD) of three SLC4 transporters, including AE1, have been resolved previously in their outward-facing (OF) state, no mammalian SLC4 structure has been reported in the inward-facing (IF) conformation. Here we present the cryoEM structures of full-length bovine AE1 with its TMD captured in both IF and OF conformations. Remarkably, both IF-IF homodimers and IF-OF heterodimers were detected. The IF structures feature downward movement in the core domain with significant unexpected elongation of TM11. Molecular modeling and structure guided mutagenesis confirmed the functional significance of residues involved in TM11 elongation. Our data provide direct evidence for an elevator-like mechanism of ion transport by an SLC4 family member.

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Section: Resultssupporting

confidence: 84%

CryoEM structures of anion exchanger 1 capture multiple states of inward- and outward-facing conformations

et al. 2022

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“…5). To strengthen the hypothesis that it is the intrinsic curvature of Piezo1 that biases it towards the curved dimple region of the RBC we also analyzed the dimple vs. rim ratio of two other RBC membrane proteins that are not intrinsically curved: the Gardos channel (Lee and MacKinnon 2018) and Band3 (Vallese et al 2022; Xia, Liu, and Zhou 2022; Arakawa et al 2015). We find no statistically significant enrichment of the Gardos channel (KCNN4) or Band3 in the dimple of RBCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Piezo1 as a force-through-membrane sensor in red blood cells

Vaisey

Banerjee

North

et al. 2022

Preprint

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Piezo1 is the stretch activated Ca2+ channel in red blood cells that mediates homeostatic volume control. Here we study the organization of Piezo1 in red blood cells using a combination of super resolution microscopy techniques and electron microscopy. Piezo1 adopts a non-uniform distribution on the red blood cell surface, with a bias towards the biconcave 'dimple'. Trajectories of diffusing Piezo1 molecules, which exhibit confined Brownian diffusion on short timescales and hopping on long timescales, also reflect a bias towards the dimple. This bias can be explained by 'curvature coupling' between the intrinsic curvature of the Piezo dome and the curvature of the red blood cell membrane. Piezo1 does not form clusters with itself, nor does it co-localize with F-actin, Spectrin or the Gardos channel. Thus, Piezo1 exhibits the properties of a force-through-membrane sensor of curvature and lateral tension in the red blood cell.

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“…The direct interaction between AE1 and GPA conceivably facilitates oligomerization and forward trafficking of the AE1-associated protein complexes that also comprise GPB, Rh/RhAG, and several other erythroid proteins. AE1-associated complexes are considered AE1-central metabolic hubs on the RBC surface [ 11 , 29 , 32 , 40 , 45 , 46 , 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

A Balance between Transmembrane-Mediated ER/Golgi Retention and Forward Trafficking Signals in Glycophorin-Anion Exchanger-1 Interaction

Hsu

Lee

Lin

et al. 2022

Cells

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Anion exchanger-1 (AE1) is the main erythroid Cl−/HCO3− transporter that supports CO2 transport. Glycophorin A (GPA), a component of the AE1 complexes, facilitates AE1 expression and anion transport, but Glycophorin B (GPB) does not. Here, we dissected the structural components of GPA/GPB involved in glycophorin-AE1 trafficking by comparing them with three GPB variants—GPBhead (lacking the transmembrane domain [TMD]), GPBtail (mainly the TMD), and GP.Mur (glycophorin B-A-B hybrid). GPB-derived GP.Mur bears an O-glycopeptide that encompasses the R18 epitope, which is present in GPA but not GPB. By flow cytometry, AE1 expression in the control erythrocytes increased with the GPA-R18 expression; GYP.Mur+/+ erythrocytes bearing both GP.Mur and GPA expressed more R18 epitopes and more AE1 proteins. In contrast, heterologously expressed GPBtail and GPB were predominantly localized in the Golgi apparatus of HEK-293 cells, whereas GBhead was diffuse throughout the cytosol, suggesting that glycophorin transmembrane encoded an ER/Golgi retention signal. AE1 coexpression could reduce the ER/Golgi retention of GPB, but not of GPBtail or GPBhead. Thus, there are forward-trafficking and transmembrane-driven ER/Golgi retention signals encoded in the glycophorin sequences. How the balance between these opposite trafficking signals could affect glycophorin sorting into AE1 complexes and influence erythroid anion transport remains to be explored.

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Architecture of the human erythrocyte ankyrin-1 complex

Cited by 53 publications

References 82 publications

CryoEM structures of anion exchanger 1 capture multiple states of inward- and outward-facing conformations

CryoEM structures of anion exchanger 1 capture multiple states of inward- and outward-facing conformations

Piezo1 as a force-through-membrane sensor in red blood cells

A Balance between Transmembrane-Mediated ER/Golgi Retention and Forward Trafficking Signals in Glycophorin-Anion Exchanger-1 Interaction

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