On the Mechanism of Band-3-Protein-Mediated Anion Transport Across the Red Blood Cell Membrane

Passow, Hermann; Fasold, H.

doi:10.1016/b978-0-08-026818-7.50035-x

Cited by 6 publications

(4 citation statements)

References 23 publications

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“…Finally, although the new model for net anion flow is quite successful in fitting the data, it is by no means unique . In particular, Passow and coworkers (Passow et al, 1980 ;Kaplan et al, 1980;Passow and Fasold, 1981) have proposed a nonconducting gate model for the anion exchange system, in which anion binding causes a reorientation of positively charged groups such that a gate is alternately open to one side or the other of the membrane. They propose that occasionally an anion may pass through the gate without causing the site reorientation, thereby giving rise to net anion flow.…”

Section: Discussionmentioning

confidence: 99%

Relationship of net chloride flow across the human erythrocyte membrane to the anion exchange mechanism.

Knauf¹,

Law²,

Marchant³

1983

The Journal of General Physiology

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The parallel effects of the anion transport inhibitor DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonate) on net chloride flow and on chloride exchange suggest that a major portion of net chloride flow takes place through the anion exchange system . The "slippage" model postulates that the rate of net any change in transport site conformation such as normally occurs during the anion exchange process . This model is successful in predicting that the anion exchange inhibitor NAP-taurine, which binds to the modifer site and inhibits the conformational change, has less effect on net chloride flow than on chloride exchange .

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Section: Discussionmentioning

confidence: 99%

Relationship of net chloride flow across the human erythrocyte membrane to the anion exchange mechanism.

Knauf¹,

Law²,

Marchant³

1983

The Journal of General Physiology

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“…transfer and modifier sites) at the intra-and extracellular side of hAE1 (10). Some of these sites (approach sites) have been implicated in redirection of the approaching substrates toward or away from the transport-triggering substrate binding site (alternating site) and could be involved in the experimentally observed self-inhibition of hAE1 at high substrate concentrations (10,42). The two sites identified here are compatible with the suggested model of an alternating (site S1) and an approach site (site S2).…”

Section: Computations Suggest Presence Of Two High Affinity Substrate Binding Sites With Potentially Different Functional Roles In Of Haementioning

confidence: 99%

Identification of multiple substrate binding sites in SLC4 transporters in the outward-facing conformation: Insights into the transport mechanism

Zhekova

Pushkin

Kayık

et al. 2021

Journal of Biological Chemistry

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Solute carrier family 4 (SLC4) transporters mediate the transmembrane transport of HCO 3 − , CO 3 2− , and Cl − necessary for pH regulation, transepithelial H + /base transport, and ion homeostasis. Substrate transport with varying stoichiometry and specificity is achieved through an exchange mechanism and/or through coupling of the uptake of anionic substrates to typically co-transported Na + . Recently solved outward-facing structures of two SLC4 members (human anion exchanger 1 [hAE1] and human electrogenic sodium bicarbonate cotransporter 1 [hNBCe1]) with different transport modes (Cl − /HCO 3 − exchange versus Na + -CO 3 2− symport) revealed highly conserved three-dimensional organization of their transmembrane domains. However, the exact location of the ion binding sites and their protein–ion coordination motifs are still unclear. In the present work, we combined site identification by ligand competitive saturation mapping and extensive molecular dynamics sampling with functional mutagenesis studies which led to the identification of two substrate binding sites (entry and central) in the outward-facing states of hAE1 and hNBCe1. Mutation of residues in the identified binding sites led to impaired transport in both proteins. We also showed that R730 in hAE1 is crucial for anion binding in both entry and central sites, whereas in hNBCe1, a Na + acts as an anchor for CO 3 2− binding to the central site. Additionally, protonation of the central acidic residues (E681 in hAE1 and D754 in hNBCe1) alters the ion dynamics in the permeation cavity and may contribute to the transport mode differences in SLC4 proteins. These results provide a basis for understanding the functional differences between hAE1 and hNBCe1 and may facilitate potential drug development for diseases such as proximal and distal renal tubular acidosis.

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“…Passow et al (1980b) have suggested that there are really two conformations of the modifier site, designated R and S, corresponding to states in which the transport site faces inward (trans) or outward (cis), respectively . Passow and Fasold (1981) note, however, that in both of these states the modifier site may face the same side of the membrane. Our evidence indicates that the two states have very similar chloride affinities.…”

Section: Involvement Of the Mother Site In Transportmentioning

confidence: 99%

Use of niflumic acid to determine the nature of the asymmetry of the human erythrocyte anion exchange system.

Knauf¹,

Mann²

1984

The Journal of General Physiology

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Niflumic acid is a noncompetitive inhibitor of chloride exchange, which binds to a site different from the transport or modifier sites. When the internal Cl -concentration is raised, at constant extracellular Cl -, the inhibitory potency of niflumic acid increases. This effect cannot be attributed to changes in membrane potential, but rather it suggests that niflumic acid binds to the anion exchange protein band 3 only when the transport site faces outward. When the chloride gradient is reversed, with Cl. > Cli, the inhibitory potency of niflumic acid decreases greatly, which indicates that the affinity of niflumic acid for band 3 with the transport site facing inward is almost 50 times less than when the transport site faces outward. Experiments in which Cli = Cl. show no significant change in the inhibition by niflumic acid when Cl-is lowered from 150 to 10 mM . These data suggest that the intrinsic dissociation constants for Cl-at the two sides of the membrane are nearly equal. Thus, the chlorideloaded transport sites have an asymmetric orientation like that of the unloaded transport sites, with -15 times more sites facing the inside than the outside. The asymmetry reflects an -1 .5 kcal/mol free energy difference between the inward-facing and outward-facing chloride-loaded forms of band 3. High concentrations of chloride (with Cl i = Clo), which partially saturate the modifier site, have no effect on niflumic acid inhibition, which indicates that chloride binds equally well to the modifier site regardless of the orientation of the transport site .

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On the Mechanism of Band-3-Protein-Mediated Anion Transport Across the Red Blood Cell Membrane

Cited by 6 publications

References 23 publications

Relationship of net chloride flow across the human erythrocyte membrane to the anion exchange mechanism.

Relationship of net chloride flow across the human erythrocyte membrane to the anion exchange mechanism.

Identification of multiple substrate binding sites in SLC4 transporters in the outward-facing conformation: Insights into the transport mechanism

Use of niflumic acid to determine the nature of the asymmetry of the human erythrocyte anion exchange system.

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