Structure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red

Syrjänen, Johanna L; Epstein, Max; Gómez, Ricardo; Furukawa, Hiro

doi:10.1038/s41467-023-39388-3

Cited by 9 publications

(3 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Structural studies have shown that the NT domain of Cx26 and Cx46/50 is folded into the pore, often parallel to the transmembrane segments, against the pore wall, as for other large-pore channels including innexins, pannexin, CALHM, and LRRC8 channels (6,7,(40)(41)(42)(43)(44)(45)(46). However cryo-EM structures of Cx30.1, and Cx43 also show the NT domain separated from the pore wall and lying parallel to the axis of the plasma membrane, thereby narrowing the pore (9, 10).…”

Section: Uncoupling Of Molecule Transport and Atomic Ion Fluxmentioning

confidence: 99%

Large-pore connexin hemichannels function as molecule transporters independently of ion conduction

Gaete,

Kumar,

Fernandez

et al. 2024

Preprint

View full text Add to dashboard Cite

Connexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore — a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.

show abstract

Section: Uncoupling Of Molecule Transport and Atomic Ion Fluxmentioning

confidence: 99%

Large-pore connexin hemichannels function as molecule transporters independently of ion conduction

Gaete,

Kumar,

Fernandez

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…These assemblies are heterogeneous in nature, with paralogs frequently adopting different oligomeric states in the same sample. The smallest assemblies were generally observed for CALHM1, where structures from different species contained between seven and nine subunits ( Demura et al, 2020 ; Ren et al, 2022 ; Ren et al, 2020 ; Syrjänen et al, 2023 ; Syrjanen et al, 2020 ). The size of the respective assemblies is generally larger for other CALHM paralogs, ranging from decamers to tridecamers ( Choi et al, 2019 ; Drożdżyk et al, 2020 ; Liu et al, 2020 ; Syrjanen et al, 2020 ).…”

Section: Introductionmentioning

confidence: 98%

Structural features of heteromeric channels composed of CALHM2 and CALHM4 paralogs

Drożdżyk,

Peter,

Dutzler

2024

eLife

View full text Add to dashboard Cite

The CALHM proteins constitute a family of large pore channels that contains six closely related paralogs in human. Two family members, CALHM1 and 3, have been associated with the release of ATP during taste sensation. Both proteins form heteromeric channels that activate at positive potential and decreased extracellular Ca 2+ concentration. Although the structures of several family members displayed large oligomeric organizations of different size, their function has in most cases remained elusive. Our previous study has identified the paralogs CALHM2, 4 and 6 to be highly expressed in the placenta and defined their structural properties as membrane proteins exhibiting features of large pore channels with unknown activation properties (Drozdzyk et al., 2020). Here we investigated whether these placental paralogs would form heteromers and characterized heteromeric complexes consisting of CALHM2 and CALHM4 subunits using specific binders as fiducial markers. Both proteins assemble with different stoichiometries with the largest population containing CALHM2 as predominant component. In these oligomers, the subunits segregate and reside in their preferred conformation found in homomeric channels. Our study has thus revealed the properties that govern the formation of CALHM heteromers in a process of potential relevance in a cellular context.

show abstract

“…These assemblies are heterogeneous in nature, with paralogs frequently adopting different oligomeric states in the same sample. The smallest assemblies were generally observed for CALHM1, where structures from different species contained between seven and nine subunits (Demura et al, 2020;Ren et al, 2022;Ren et al, 2020;Syrjänen et al, 2023;Syrjanen et al, 2020). The size of the respective assemblies is generally larger for other CALHM paralogs, ranging from decamers to tridecamers (Choi et al, 2019;Drozdzyk et al, 2020;Liu et al, 2020;Syrjanen et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Structural features of heteromeric channels composed of CALHM2 and CALHM4 paralogs

Drożdżyk,

Peter,

Dutzler

2024

Preprint

View full text Add to dashboard Cite

The CALHM proteins constitute a family of large pore channels that contains six closely related paralogs in human. Two family members, CALHM1 and 3, have been associated with the release of ATP during taste sensation. Both proteins form heteromeric channels that activate at positive potential and decreased extracellular Ca2+concentration. Although the structures of several family members displayed large oligomeric organizations of different size, their function has in most cases remained elusive. Our previous study has identified the paralogs CALHM2, 4 and 6 to be highly expressed in the placenta and defined their structural properties as membrane proteins exhibiting features of large pore channels with unknown activation properties (Drozdzyk et al., 2020). Here we investigated whether these placental paralogs would form heteromers and characterized heteromeric complexes consisting of CALHM2 and CALHM4 subunits using specific binders as fiducial markers. Both proteins assemble with different stoichiometries with the largest population containing CALHM2 as predominant component. In these oligomers, the subunits segregate and reside in their preferred conformation found in homomeric channels. Our study has thus revealed the properties that govern the formation of CALHM heteromers in a process of potential relevance in a cellular context.

show abstract

Structure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red

Cited by 9 publications

References 62 publications

Large-pore connexin hemichannels function as molecule transporters independently of ion conduction

Large-pore connexin hemichannels function as molecule transporters independently of ion conduction

Structural features of heteromeric channels composed of CALHM2 and CALHM4 paralogs

Structural features of heteromeric channels composed of CALHM2 and CALHM4 paralogs

Contact Info

Product

Resources

About