Abstract
The solute carrier SLC4 family consists of 10 members, nine of which are transporters, including three Na+-independent Cl−/ exchangers AE1, AE2, and AE3, five Na+-coupled transporters NBCe1, NBCe2, NBCn1, NBCn2, and NDCBE, as well as “AE4” whose Na+-dependence remains controversial. The SLC4 transporters play critical roles in pH regulation and transepithelial movement of electrolytes with a broad range of demonstrated physiological relevances. Dysfunctions of these transporters are associated with a series of human diseases. During the past decades, tremendous amount of effort has been undertaken to investigate the topological organization of the SLC4 transporters in the plasma membrane. Based upon the proposed topology models, mutational and functional studies have identified important structural elements likely involved in the ion translocation by the SLC4 transporters. In the present article, we review the advances during the past decades in understanding the structure and function of the SLC4 transporters.
Highlights
It is fundamentally important to maintain acid-base homeostasis in the body
Except for SLC4A11 encoding BTR1 which likely mediates electrogenic Na+-coupled borate transport (Parker et al, 2001; Park et al, 2004) and/or electrogenic NH3/H+ cotransport (Ogando et al, 2013; Zhang et al, 2015; for review, see Patel and Parker, 2015), the other nine (SLC4A1-5 and SLC4A7-10) encode HCO−3 transporters that are either Na+-independent or Na+-dependent (Figure 1)
The authors proposed that the Nt domain of AE1, and likely other solute carrier 4 (SLC4) family members, does not contain a substrate entry tunnel that is essential for the transport activity of the proteins
Summary
It is fundamentally important to maintain acid-base homeostasis in the body. The solute carrier 4 (SLC4) family represents a major group of bicarbonate transporters. The Nt domain of AE2 contains multiple structural elements important for the acute regulation of transport activity by changes in intracellular and extracellular pH (see discussion in “Structural variations in SLC4 transporters”). As will be discussed in details in section “Structural variations in SLC4,” the Nt domains of the NCBTs contain multiple optional structural elements (OSEs), some of which contain binding sites for regulatory protein partners or can modulate the intrinsic activity of the transporters.
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