Structure and Function of SLC4 Family HCO3- Transporters

Liu, Ying; Yang, Jichun; Chen, Li Ming

doi:10.3389/fphys.2015.00355

Cited by 56 publications

(56 citation statements)

References 192 publications

(337 reference statements)

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“…To the best of our knowledge, no studies have reported the modulation of SLC4 members by intracellular Zn 2+ through interactions with the cytoplasmic domain. The cytoplasmic domain of SLC4 transporters is only present in animals, adding to the common perception of an advanced regulatory role of the overall N-terminal cytoplasmic domain in higher organisms 12 . Our data reveal multiple Zn 2+ -binding sites in ntcNDCBE and ntcNCBE, all with affinities in the low micromolar range.…”

Section: Discussionmentioning

confidence: 99%

“…The primary structure of the isolated cytoplasmic regulatory domains shares lower sequence identity across the SLC4 family, than the transmembrane regions. Based on sequences with either low or high sequence variability, the cytoplasmic domains have been divided into regions referred to as constant regions (CRs) and variable regions (VRs) 12 . The VRs mainly include the different functional and regulatory motifs of SLC4 family members and their isoforms 13 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Alvadia

Sommer

Bjerregaard-Andersen

et al. 2017

Sci Rep

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The sodium-driven chloride/bicarbonate exchanger (NDCBE) is essential for maintaining homeostatic pH in neurons. The crystal structure at 2.8 Å resolution of the regulatory N-terminal domain of human NDCBE represents the first crystal structure of an electroneutral sodium-bicarbonate cotransporter. The crystal structure forms an equivalent dimeric interface as observed for the cytoplasmic domain of Band 3, and thus establishes that the consensus motif VTVLP is the key minimal dimerization motif. The VTVLP motif is highly conserved and likely to be the physiologically relevant interface for all other members of the SLC4 family. A novel conserved Zn2+-binding motif present in the N-terminal domain of NDCBE is identified and characterized in vitro. Cellular studies confirm the Zn2+ dependent transport of two electroneutral bicarbonate transporters, NCBE and NBCn1. The Zn2+ site is mapped to a cluster of histidines close to the conserved ETARWLKFEE motif and likely plays a role in the regulation of this important motif. The combined structural and bioinformatics analysis provides a model that predicts with additional confidence the physiologically relevant interface between the cytoplasmic domain and the transmembrane domain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Alvadia

Sommer

Bjerregaard-Andersen

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…They arise from two alternative promotors, three optional structural elements (cassettes I-III), and respective alternative splicing ( Figure S1 C) ( Liu et al., 2013 , Parker and Boron, 2013 , Pushkin et al., 1999 ). SLC4A7 is expressed in several cell types and tissues including brain, heart, and kidney ( Damkier et al., 2007 , Liu et al., 2015 , Pushkin et al., 1999 , Romero et al., 2013 ). Although data on SLC4A7 expression in the immune system are scarce, there is evidence for a specific role in macrophages.…”

Section: Main Textmentioning

confidence: 99%

The Bicarbonate Transporter SLC4A7 Plays a Key Role in Macrophage Phagosome Acidification

Sedlyarov

Eichner

Gottardi

et al. 2018

Cell Host & Microbe

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SummaryMacrophages represent the first line of immune defense against pathogens, and phagosome acidification is a necessary step in pathogen clearance. Here, we identified the bicarbonate transporter SLC4A7, which is strongly induced upon macrophage differentiation, as critical for phagosome acidification. Loss of SLC4A7 reduced acidification of phagocytosed beads or bacteria and impaired the intracellular microbicidal capacity in human macrophage cell lines. The phenotype was rescued by wild-type SLC4A7, but not by SLC4A7 mutants, affecting transport capacity or cell surface localization. Loss of SLC4A7 resulted in increased cytoplasmic acidification during phagocytosis, suggesting that SLC4A7-mediated, bicarbonate-driven maintenance of cytoplasmic pH is necessary for phagosome acidification. Altogether, we identify SLC4A7 and bicarbonate-driven cytoplasmic pH homeostasis as an important element of phagocytosis and the associated microbicidal functions in macrophages.

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“…Two genes with known rare variants shared between the proband and the proband's sister are presented in Table II. The first identical mutation in the proband and the proband's sister was on solute carrier family 4 member 1 (SLC4A1; GenBank ID NM_000342.3) which is a band 3 cytoplasmic domain and phosphotransferase/anion transporter (19). A heretogenous missense variant c.388G>A (p.Gly130Arg, rs121912749) in exon 6 of SLC4A1 was observed.…”

Section: Resultsmentioning

confidence: 99%

Identification of mutations in SLC4A1, GP1BA and HFE in a family with venous thrombosis of unknown cause by next‑generation sequencing

et al. 2018

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Various risk factors, including high age, female gender, obesity and certain genetic defects have been linked to venous thrombosis. A Taiwanese family with venous thrombosis of unknown cause were enrolled in the present study. In this pedigree, two women without any specific underlying diseases suffered from venous thrombotic events at the same age. No specific risk factors or coagulation abnormalities were identified. The main proband's younger brother also had intestinal arterial thrombosis at 54 years of age. Therefore, it was hypothesized that familial genetic defects may be the cause of venous thrombosis within this family. Blood samples collected from certain members of this pedigree were subjected to whole-exome sequencing, and three genetic variants were identified, including a missense variant of solute carrier family 4 member 1 (SLC4A1) (c.388G>A), a deletion on glycoprotein Ib platelet α subunit (GP1BA) (c.1322_1344del23) and an insertion in the splice site of homeostatic iron regulator (HFE). To date, none of these three genetic variants have been reported to be associated with venous thrombosis, to the best of our knowledge. The present study suggests that these genetic variants of SLC4A1, GP1BA and HFE may be associated with venous thrombosis in an Asian pedigree.

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Structure and Function of SLC4 Family HCO3- Transporters

Cited by 56 publications

References 192 publications

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

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

The Bicarbonate Transporter SLC4A7 Plays a Key Role in Macrophage Phagosome Acidification

Identification of mutations in SLC4A1, GP1BA and HFE in a family with venous thrombosis of unknown cause by next‑generation sequencing

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