The crystal structure of the regulatory domain of the human sodium-driven chloride/bicarbonate exchanger

Alvadia, Carolina; Sommer, T.; Bjerregaard-Andersen, Kaare; Damkier, Helle Hasager; Montrasio, Michele; Aalkjær, Christian; Morth, J. Preben

doi:10.1038/s41598-017-12409-0

Cited by 9 publications

(7 citation statements)

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“…Given that the EL3 structure was not resolved in other SLC4 transporters, its role in their dimerization is uncertain, although based on the sequencing homology EL3 plays a potentially similar role in other Na + -dependent SLC4 transporters. In addition, our data complement the reported dimerization of recombinant CD of NDCBE 29 supporting a potential involvement of NDCBE CD in dimerization similar to the dimerization of AE1 CD 15 . In SLC26A9 key interactions between the two monomers are thought to be mediated by the CD STAS domains 21 .…”

Section: Discussionsupporting

confidence: 84%

Cryo-EM structure of the sodium-driven chloride/bicarbonate exchanger NDCBE

et al. 2021

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SLC4 transporters play significant roles in pH regulation and cellular sodium transport. The previously solved structures of the outward facing (OF) conformation for AE1 (SLC4A1) and NBCe1 (SLC4A4) transporters revealed an identical overall fold despite their different transport modes (chloride/bicarbonate exchange versus sodium-carbonate cotransport). However, the exact mechanism determining the different transport modes in the SLC4 family remains unknown. In this work, we report the cryo-EM 3.4 Å structure of the OF conformation of NDCBE (SLC4A8), which shares transport properties with both AE1 and NBCe1 by mediating the electroneutral exchange of sodium-carbonate with chloride. This structure features a fully resolved extracellular loop 3 and well-defined densities corresponding to sodium and carbonate ions in the tentative substrate binding pocket. Further, we combine computational modeling with functional studies to unravel the molecular determinants involved in NDCBE and SLC4 transport.

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Section: Discussionsupporting

confidence: 84%

Cryo-EM structure of the sodium-driven chloride/bicarbonate exchanger NDCBE

et al. 2021

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“…Figure 1 B shows a model of the 3‐dimension structure of the Nt core of NBCe1 simulated based on the crystal structure of the Nt of human NDCBE (Alvadia et al . 2017). Cassette I is located in a poorly folded loop.…”

Section: Resultsmentioning

confidence: 99%

IRBIT activates NBCe1‐B by releasing the auto‐inhibition module from the transmembrane domain

Wang

et al. 2020

The Journal of Physiology

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Key points The electrogenic Na+/HCO3−cotransporter NBCe1‐B is widely expressed in many tissues, including pancreas, submandibular gland, brain, heart, etc. NBCe1‐B has very low activity under basal condition due to auto‐inhibition, but can be fully activated by protein interaction with the IP3R‐binding protein released with inositol 1,4,5‐trisphosphate (IRBIT). The structural components of the auto‐inhibition domain and the IRBIT‐binding domain of NBCe1‐B are finely characterized based on systematic mutations in the present study and data from previous studies. Reducing negative charges on the cytosol side of the transmembrane domain greatly decreases the magnitude of the auto‐inhibition of NBCe1‐B. We propose that the auto‐inhibition domain functions as a brake module that inactivates NBCe1‐B by binding to, via electrostatic attraction, the transmembrane domain; IRBIT activates NBCe1‐B by releasing the brake from the transmembrane domain via competitive binding to the auto‐inhibition domain. Abstract The electrogenic Na+/HCO3− cotransporter NBCe1‐B is widely expressed in many tissues in the body. NBCe1‐B exhibits only basal activity due to the action of the auto‐inhibition domain (AID) in its unique amino‐terminus. However, NBCe1‐B can be activated by interaction with the IP3R‐binding protein released with inositol 1,4,5‐trisphosphate (IRBIT). Here, we investigate the molecular mechanism underlying the auto‐inhibition of NBCe1‐B and its activation by IRBIT. The IRBIT‐binding domain (IBD) of NBCe1‐B spans residues 1−52, essentially consisting of two arms, one negatively charged (residues 1−24) and the other positively charged (residues 40−52). The AID mainly spans residues 40−85, overlapping with the IBD in the positively charged arm. The magnitude of auto‐inhibition of NBCe1‐B is greatly decreased by manipulating the positively charged residues in the AID or by replacing a set of negatively charged residues with neutral ones in the transmembrane domain. The interaction between IRBIT and NBCe1‐B is abolished by mutating a set of negatively charged Asp/Glu residues (to Asn/Gln) plus a set of Ser/Thr residues (to Ala) in the PEST domain of IRBIT. However, this interaction is not affected by replacing the same set of Ser/Thr residues in the PEST domain with Asp. We propose that: (1) the AID, acting as a brake, binds to the transmembrane domain via electrostatic interaction to slow down NBCe1‐B; (2) IRBIT activates NBCe1‐B by releasing the brake from the transmembrane domain.

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“…The next transport mechanism comprises electrogenic Na + /HCO 3 − -cotransport performed by NCBT transporter proteins NBCe1 and NBCe2 encoded by SLC4A4 and SLC4A5. The fourth way is the electroneutral Na + - HCO 3 − cotransport or Na + -driven Cl − /HCO 3 − exchange through the transporter protein encoded by SLC4A10 [ 39 , 40 , 41 ]. The fifth mechanisms involves electroneutral Cl − /HCO 3 − exchangers that also can exchange either I − , NO 3 − , SCN − , or formate encoded by SLC26A (Pendrin) or NO 3 − , OH − , SO 4 2− , oxalate, and formate (SLC26A6).…”

Section: Bicarbonate Transportmentioning

confidence: 99%

Transport and Use of Bicarbonate in Plants: Current Knowledge and Challenges Ahead

Poschenrieder

Fernández

Rubio

et al. 2018

IJMS

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Bicarbonate plays a fundamental role in the cell pH status in all organisms. In autotrophs, HCO3− may further contribute to carbon concentration mechanisms (CCM). This is especially relevant in the CO2-poor habitats of cyanobacteria, aquatic microalgae, and macrophytes. Photosynthesis of terrestrial plants can also benefit from CCM as evidenced by the evolution of C4 and Crassulacean Acid Metabolism (CAM). The presence of HCO3− in all organisms leads to more questions regarding the mechanisms of uptake and membrane transport in these different biological systems. This review aims to provide an overview of the transport and metabolic processes related to HCO3− in microalgae, macroalgae, seagrasses, and terrestrial plants. HCO3− transport in cyanobacteria and human cells is much better documented and is included for comparison. We further comment on the metabolic roles of HCO3− in plants by focusing on the diversity and functions of carbonic anhydrases and PEP carboxylases as well as on the signaling role of CO2/HCO3− in stomatal guard cells. Plant responses to excess soil HCO3− is briefly addressed. In conclusion, there are still considerable gaps in our knowledge of HCO3− uptake and transport in plants that hamper the development of breeding strategies for both more efficient CCM and better HCO3− tolerance in crop plants.

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The crystal structure of the regulatory domain of the human sodium-driven chloride/bicarbonate exchanger

Cited by 9 publications

References 50 publications

Cryo-EM structure of the sodium-driven chloride/bicarbonate exchanger NDCBE

Cryo-EM structure of the sodium-driven chloride/bicarbonate exchanger NDCBE

IRBIT activates NBCe1‐B by releasing the auto‐inhibition module from the transmembrane domain

Transport and Use of Bicarbonate in Plants: Current Knowledge and Challenges Ahead

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