The serum iron level in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates iron absorption and recycling by inducing ferroportin internalization and degradation 1 . Aberrant ferroportin activity can lead to diseases of iron overload, like hemochromatosis, or iron limitation anemias 2 . Here, we determined cryogenic electron microscopy (cryo-EM) structures of ferroportin in lipid nanodiscs, both in the apo state and in complex with cobalt, an iron mimetic, and hepcidin. These structures and accompanying molecular dynamics simulations identify two metal binding sites within the N- and C-domains of ferroportin. Hepcidin binds ferroportin in an outward-open conformation and completely occludes the iron efflux pathway to inhibit transport. The carboxy-terminus of hepcidin directly contacts the divalent metal in the ferroportin C-domain. We further show that hepcidin binding to ferroportin is coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. These results suggest a model for hepcidin regulation of ferroportin, where only iron loaded ferroportin molecules are targeted for degradation. More broadly, our structural and functional insights are likely to enable more targeted manipulation of the hepcidin-ferroportin axis in disorders of iron homeostasis.

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A first testing ground for QED in the combined presence of a strong Coulomb field and a strong magnetic field is provided by the precise measurement of the hyperfine structure splitting of hydrogenlike 209 Bi. We present a complete calculation of the one-loop self-energy correction to the first-order hyperfine interaction for various nuclear charges. In the low-Z regime we almost perfectly agree with the Za expansion, but for medium and high Z there is a substantial deviation.PACS numbers: 31.30. Gs, 31.15.Ar, 31.30.Jv Very recently it was reported that for the first time the hyperfine structure splitting of a hydrogenlike high-Z atom was observed with a high relative accuracy of about 10 24 at the ESR at GSI, Darmstadt. The transition energy of the ground state hyperfine structure splitting of 209 Bi 821 was measured to be DE 5.0840͑8͒ eV [1]. This has challenged theory to perform calculations with comparable accuracy, including also one-loop QED corrections. The new experimental situation opens up a possibility to perform a novel test of QED in a combined strong magnetic field and a strong Coulomb field.The leading QED effects are of two types: vacuum polarization and self-energy corrections. The vacuum polarization correction is relatively straightforward to compute, using an Uehling-like approximation. This contribution was calculated to be DE VP 10.035 eV quite recently [2]. The remaining Wichmann-Kroll contribution is very small. The one-loop self-energy correction, on the other hand, is more difficult to elaborate, and earlier calculations using an Za expansion of the Coulomb field are correct only up to order a͑Za͒ 2 mc 2 [3-7]. For heavy elements such an expansion is not reliable. Therefore it is necessary to calculate the self-energy contribution to all orders in Za. In this Letter we present the first complete calculation of this type for different nuclear charges ranging from Z 1 to Z 92 using similar techniques as published earlier in Refs. [8][9][10][11][12].First we give a brief outline of the computation of the self-energy correction and later we discuss the numerical results. A more detailed analysis of the calculation of QED corrections to the hyperfine interaction will be presented in a forthcoming paper [13].In a previous paper it was shown that the unrenormalized self-energy correction for a bound electron state can be written in Feynman gauge as [9] E bou ͑a͒ 2 awhere a m a m ͑1 2 a ? a͒, C ͓l͔ q is the q component of the spherical angular tensor of order l, j l ͑kr͒ denotes the spherical Bessel function of order l, and ja͘ represents the reference state. There is also a corresponding mass counter term.To calculate the self-energy corrections to the hyperfine structure we treat the magnetic potential A͑r ͒ as a perturbation of the system. This perturbation will affect the binding energy of the bound electron, the wave function, and the bound propagator as already sketched out in Ref. [14]

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