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Mechanism of Ca²⁺ transport by ferroportin.

ABSTRACT: Ferroportin (Fpn) is a transporter that releases ferrous ion (Fe²⁺) from cells and is important for homeostasis of iron in circulation. Export of one Fe²⁺ by Fpn is coupled to import of two H⁺ to maintain charge balance. Here, we show that human Fpn (HsFpn) binds to and mediates Ca²⁺ transport. We determine the structure of Ca²⁺-bound HsFpn and identify a single Ca²⁺ binding site distinct from the Fe²⁺ binding sites. Further studies validate the Ca²⁺ binding site and show that Ca²⁺ transport is not coupled to transport of another ion. In addition, Ca²⁺ transport is significantly inhibited in the presence of Fe²⁺ but not vice versa. Function of Fpn as a Ca²⁺ uniporter may allow regulation of iron homeostasis by Ca²⁺.

SUBMITTER: Shen J

PROVIDER: S-EPMC9883014 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Mechanism of Ca2+ transport by ferroportin.

Shen Jiemin J Wilbon Azaan Saalim AS Zhou Ming M Pan Yaping Y

eLife 20230117

Ferroportin (Fpn) is a transporter that releases ferrous ion (Fe2+) from cells and is important for homeostasis of iron in circulation. Export of one Fe2+ by Fpn is coupled to import of two H+ to maintain charge balance. Here, we show that human Fpn (HsFpn) binds to and mediates Ca2+ transport. We determine the structure of Ca2+-bound HsFpn and identify a single Ca2+ binding site distinct from the Fe2+ binding sites. Fu ...[more]

PMID: 36648329

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Project description:BackgroundWhile calcium is known to play a crucial role in mammalian sperm physiology, how it flows in and out of the male gamete is not completely understood. Herein, we investigated the involvement of Na+/Ca2+ exchangers (NCX) in mammalian sperm capacitation. Using the pig as an animal model, we first confirmed the presence of NCX1 and NCX2 isoforms in the sperm midpiece. Next, we partially or totally blocked Ca2+ outflux (forward transport) via NCX1/NCX2 with different concentrations of SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline; 0, 0.5, 5 and 50 µM) and Ca2+ influx (reverse transport) with SN6 (ethyl 2-[[4-[(4-nitrophenyl)methoxy]phenyl]methyl]-1,3-thiazolidine-4-carboxylate; 0, 0.3, 3 or 30 µM). Sperm were incubated under capacitating conditions for 180 min; after 120 min, progesterone was added to induce the acrosome reaction. At 0, 60, 120, 130, and 180 min, sperm motility, membrane lipid disorder, acrosome integrity, mitochondrial membrane potential (MMP), tyrosine phosphorylation of sperm proteins, and intracellular levels of Ca2+, reactive oxygen species (ROS) and superoxides were evaluated.ResultsPartial and complete blockage of Ca2+ outflux and influx via NCX induced a significant reduction of sperm motility after progesterone addition. Early alterations on sperm kinematics were also observed, the effects being more obvious in totally blocked than in partially blocked samples. Decreased sperm motility and kinematics were related to both defective tyrosine phosphorylation and mitochondrial activity, the latter being associated to diminished MMP and ROS levels. As NCX blockage did not affect the lipid disorder of plasma membrane, the impaired acrosome integrity could result from reduced tyrosine phosphorylation.ConclusionsInhibition of outflux and influx of Ca2+ triggered similar effects, thus indicating that both forward and reverse Ca2+ transport through NCX exchangers are essential for sperm capacitation.

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Mechanism of Ca²⁺ transport by ferroportin.

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Mechanism of Ca<sup>2+</sup> transport by ferroportin.

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