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The Iron Maiden. Cytosolic Aconitase/IRP1 Conformational Tran- 2 Sition in the Regulation of Ferritin Translation and Iron Hemosta- 3 Sis 4

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The Iron Maiden. Cytosolic Aconitase/IRP1 Conformational Tran- 2 Sition in the Regulation of Ferritin Translation and Iron Hemosta- 3 Sis 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.28.454104; this version posted July 28, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Article 1 The iron maiden. Cytosolic aconitase/IRP1 conformational tran- 2 sition in the regulation of ferritin translation and iron hemosta- 3 sis 4 Cécilia Hognon1, Emmanuelle Bignon1, Guillaume Harle2, Nadège Touche2, Stéphanie Grandemange2, * and Anto- 5 nio Monari1,3* 6 1 Université de Lorraine and CNRS, UMR 7019 LPCT, F-5400 Nancy, France 7 2 Université de Lorraine and CNRS, UMR 7039 CRAN, F-54000 Nancy, France 8 3 Université de Paris and CNRS, ITODYS, F-75006 Paris, France. 9 * Correspondence: SG [email protected] , AM [email protected] 10 Abstract: Maintaining iron homeostasis is fundamental for almost all living being, and its deregu- 11 lation correlates With severe and debilitating pathologies. The process is made more complicated by 12 the omnipresence of iron and by its role as a fundamental component of a number of crucial metallo 13 proteins. The response to modifications in the amount of the free iron pool is performed via the 14 inhibition of ferritin translation by sequestering consensus messenger RNA (mRNA) sequences. In 15 turn this is regulated by the iron-sensitive conformational equilibrium betWeen aconitase and IRP, 16 mediated by the presence of an iron-sulfur cluster. In this contribution We analyze by full-atom 17 molecular dynamics simulation, the factors leading to both the interaction With mRNA, and the 18 conformational transition. Furthermore, the role of the iron-sulfur cluster in driving the conforma- 19 tional transition is assessed by obtaining the related free energy profile via enhanced sampling mo- 20 lecular dynamics simulations. 21 Keywords: Molecular dynamics; free energy profiles; iron homeostasis; aconitase; IRP; messenger 22 RNA. 23 24 1. Introduction 25 Iron is a fundamental element, Which is involved in key biological processes [1–4], 26 such as oxygen transport in hemoglobin, electron transfer, muscle contraction, and serves 27 as a co-factor for many enzymes. As a matter of fact, a number of iron-containing protein 28 has been identified, and the latter are involved in extremely diverse functions [5]. For in- 29 stance, Fe-S clusters have been assigned both a structural and redox role in DNA repair 30 proteins and other enzymes [6–8]. In addition to protein-embedded iron, a limited quan- 31 tity of free iron is also available in cells, in What is called free iron pool (FIP) [9–11]. FIP is 32 constituted by iron in both II and III oxidation states and the metal is usually complexed 33 with different, and not yet very well characterized, ligands and chelatants [12]. Despite its 34 limited characterization, FIP is essential for cells viability, and its dysregulation may be 35 correlated With cellular instability, and at a systemic level, With the development of debil- 36 itating pathologies, including cancer [13–16] and mitochondria failure [17,18]. On the 37 other hand, FIP iron accumulation, and especially the accumulation of Fe2+ is also inducing 38 considerable oxidative stress, most notably due to the production of peroxyl radical via 39 Fenton reaction [19]. As a logic consequence cells have developed complex regulatory ma- 40 chineries to stabilize and regulate the amount of FIP [20,21]. 41 It is recognized that the regulation of iron homeostasis involves tuning the expression 42 of several genes involved in storage, outtake and intake of iron such as ferritin H and L 43 (involved in iron storage), ferroportin (involved in iron outtake) and transferrin receptor 44 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.28.454104; this version posted July 28, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. (TFR1 involved in iron uptake) [22,23]. These regulations have to be monitored rapidly to 45 react to all changes in iron availability. Thus, cells possess a post-transcriptional regula- 46 tory mechanism that involves the binding of messenger RNA (mRNA) consensus sites 47 present in untranslated sequences (UTR) of the iron regulatory genes by specific proteins 48 [24–28]. 49 Indeed, in presence of high iron level, cytosolic aconitase (cAco) embeds a Fe-S clus- 50 ter Which confers an enzymatic activity catalyzing the isomerization of citrate in cis-citrate 51 via cis-aconitate. Conversely, When the FIP level decreases cAco loses the Fe-S cluster trig- 52 gering a conformational transition that is accompanied With the loss of the catalytic activ- 53 ity [29,30]. Furthermore, in its iron-free conformation the protein, knoWn as iron regulat- 54 ing protein 1 (IRP1), is able to bind a hairpin mRNA sequence, the iron regulating element 55 (IRE) Which is highly conserved and present in the ferritin, ferroportin and transferrin 56 receptor transcripts of vertebrates, While it is absent in non-vertebrate despite the conser- 57 vation of the cAco/IRP1 equilibrium [31–33]. The binding of IRP1 on IRE, located in 5’UTR, 58 obviously induces a blockage of ferritin and ferroportin translation, leading to their doWn- 59 expression and ultimately to the increase of FIP level (Scheme 1) [34,35]. On the contrary, 60 the binding of IRP1 on the IRE present in the 3’UTR of the transferrin receptor leads to 61 mRNA stabilization and thus to an elevation of its translation allowing an increase in iron 62 uptake. Once the cellular iron concentration has risen again sufficiently, the equilibrium 63 betWeen cAco and IRP1 is altered releasing IRE and reinstating the translation of these 64 genes. 65 66 Cytosolic aconitase IRP1 (cAco) Free iron pool (FIP) available in cells FIP Enzymatic activity IRE Binding mRNA 5’ UTR 3’ UTR - Ferritin H / Ferritin L Translation blockage - Ferroportin Translation mRNA 5’ UTR 3’ UTR Stabilization of mRNA - Transferrin receptor 67 Scheme 1. Mechanism of the regulation of FIP level by the cAco/IRP1 conformational 68 equilibrium and the binding With IRE mRNA. 69 70 From a structural point of view, different crystal structures of cAco and IRP1, also 71 complexed With the IRE hairpin sequence, have been resolved [7,36]. Evidencing that the 72 conformational translation responsible for homeostasis regulation can be summarized as 73 the passage from a closed (cAco) to an open (IRP1) structure Which exposes the RNA 74 binding motifs. However, some important questions still hold concerning the molecular 75 bases driving the mechanisms. In particular the role of the Fe-S cluster in stabilizing the 76 cAco form has not been clearly evaluated, as well as the reasons leading to the selective 77 interaction With IRE consensus sequence. Furthermore, the flexibility and intrinsic 78 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.28.454104; this version posted July 28, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. dynamic of IRP1 bound and unbound to RNA is also lacking and could provide important 79 insights to clarify its mechanism of action. 80 In this contribution We resort to all atom classical molecular dynamic (MD) simula- 81 tions to explore the behavior of cAco, IRP1, and IRE and their mutual interactions using 82 the consensus IRE of the ferritin transcript as a model. Furthermore, We also provide en- 83 hanced sampling MD simulation to assess the free energy profile for the cAco à IRP1 84 transition in presence and in absence of a Fe-S cluster, hence assessing the thermodynam- 85 ics factors at the base of the first step of iron hemostasis. 86 The deregulation of the cellular iron level is associated to a series of debilitating pa- 87 thologies, including cancer, yet its current comprehension, from a structural point of vieW, 88 is still far from being ideal. Unraveling the key biophysical effects behind the complex 89 structural transitions taking place may lead, in the future, to the development of novel 90 therapeutic strategies, also involving therapeutic mRNA protocols. 91 92 2. Materials and Methods 93 The initial structure of the IRP1/IRE complex has been obtained from pdb code 3snp [7], 94 the initial conditions for the MD simulations of the isolated IRP1 and IRE moieties have 95 been obtained from the same crystal structure. The structure of the human cAco enzyme 96 has been instead retrieved from the pdb code 2b3y [36]. Even if the tWo structure are re- 97 ferring to different organisms the sequence homology is exceeding 95% hence assuring 98 meaningful comparison. 99 For all the MD simulations the amber2014 force field has been considered [37] while in the 100 case of nucleic acid the bsc1 corrections [38,39] to enhance the description of the backbone 101 parameters have also been taken into account. The Fe-S (4Fe-4S) cluster has been modeled 102 using a specifically tailored set of parameters designed by Carvalho and SWart [40,41] and 103 already used by some of us in the modeling of endonucleases [42]. All the systems have 104 then been solvated in a cubic TIP3P [43] water box with a 9 Å buffer and K+ cations have 105 been added to ensure electroneutrality.
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