title: Local packing modulates diversity of iron pathways and cooperative behavior in eukaryotic and prokaryotic ferritins.
abstract: Ferritin-like molecules show a remarkable combination of the evolutionary conserved activity of iron uptake and release that engage different pores in the conserved ferritin shell. It was hypothesized that pore selection and iron traffic depend on dynamic allostery with no conformational changes in the backbone. In this study, we detect the allosteric networks in Pseudomonas aeruginosa bacterioferritin (BfrB), bacterial ferritin (FtnA), and bullfrog M and L ferritins (Ftns) by a network-weaving algorithm (NWA) that passes threads of an allosteric network through highly correlated residues using hierarchical clustering. The residue-residue correlations are calculated in the packing-on elastic network model that introduces atom packing into the common packing-off model. Applying NWA revealed that each of the molecules has an extended allosteric network mostly buried inside the ferritin shell. The structure of the networks is consistent with experimental observations of iron transport: The allosteric networks in BfrB and FtnA connect the ferroxidase center with the 4-fold pores and B-pores, leaving the 3-fold pores unengaged. In contrast, the allosteric network directly links the 3-fold pores with the 4-fold pores in M and L Ftns. The majority of the network residues are either on the inner surface or buried inside the subunit fold or at the subunit interfaces. We hypothesize that the ferritin structures evolved in a way to limit the influence of functionally unrelated events in the cytoplasm on the allosteric network to maintain stability of the translocation mechanisms. We showed that the residue-residue correlations and the resultant long-range cooperativity depend on the ferritin shell packing, which, in turn, depends on protein sequence composition. Switching from the packing-on to the packing-off model reduces correlations by 35%-38% so that no allosteric network can be found. The influence of the side-chain packing on the allosteric networks explains the diversity in mechanisms of iron traffic suggested by experimental approaches.
authors.affiliation: Infection Innovative Medicine, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA.
authors.forename: Anatoly M
authors.initials: AM
authors.lastname: Ruvinsky
authors.affiliation: Center for Bioinformatics, The University of Kansas, Lawrence, Kansas 66047, USA.
authors.forename: Ilya A
authors.initials: IA
authors.lastname: Vakser
authors.affiliation: Department of Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Rivera
mesh_terms: D000465:Algorithms; D000494:Allosteric Regulation; D005057:Eukaryotic Cells / Q000737:chemistry / Q000378:metabolism*; D005293:Ferritins / Q000737:chemistry / Q000378:metabolism*; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011387:Prokaryotic Cells / Q000737:chemistry / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000737:chemistry / Q000378:metabolism
chemical_list: D005293:Ferritins; D007501:Iron