caa a22 4500 60550749X CHVBK 20210128100632.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s00775-015-1256-4 doi (NATIONALLICENCE)springer-10.1007/s00775-015-1256-4 Detailed molecular dynamics simulations of human transferrin provide insights into iron release dynamics at serum and endosomal pH [Elektronische Daten] [Haleh Abdizadeh, Ali Atilgan, Canan Atilgan] Human serum transferrin (hTf) transports ferric ions in the blood stream and delivers them to cells via receptor-mediated endocytosis. hTf is folded into two homologous lobes; we utilize three of the available crystal structures delineating large conformational changes involved in iron binding/dissociation. We address the problems of whether the release process follows the same trend at serum (~7.4) and endosomal (~5.6) pH, and if there is communication between the lobes. In the absence of the transferrin receptor, we study the dynamics of the full structure as well as the separate lobes in different closed, partially open, and open conformations under neutral and endosomal pH conditions. Results corroborate those experimental observations underscoring the distinguishing effect of pH on the dynamics of hTf. Furthermore, in a total of 2μs molecular dynamics simulations, residue fluctuations elucidate the cross talk between the lobes correlated by the peptide linker bridging them at serum pH, while their correlations are lost under endosomal conditions. At serum pH, interplay between relative mobility of the lobes is correlated with iron release rates, rendering the initial conformational change an important contributor to the dynamics under these conditions. Interestingly, C-lobe opening lags behind that of the N-lobe as long as there is at least one iron bound, making the more stable C-lobe an attractive target for recognition by receptors. At endosomal pH, both lobes readily open, making irons available for delivery. SBIC, 2015 Nonheme iron-binding glycoprotein nationallicence Conformational change nationallicence Lobe-lobe cross talk nationallicence Correlated motions nationallicence Endosomal pH nationallicence A : Apo human transferrin nationallicence H : Holo human transferrin nationallicence H** : Holo human transferrin with locked irons nationallicence H* : One tyrosine contacting Fe+3 from each lobe deprotonated (Y188 and Y517) nationallicence HFe+N : Fe+3 only in N-lobe nationallicence HFe+C : Fe+3 only in C-lobe nationallicence HN : N-lobe only nationallicence Fe+3 included nationallicence HC : C-lobe only nationallicence H† : Holo human transferrin at endosomal pH nationallicence hTf : Human serum transferrin nationallicence PO : Partially open human transferrin nationallicence RMSD : Root mean square deviation nationallicence RMSF : Root mean square fluctuation nationallicence Tf : Transferrin family nationallicence TfR : Transferrin receptor nationallicence Abdizadeh Haleh Faculty of Engineering and Natural Sciences, Sabanci University, 34956, Tuzla, Istanbul, Turkey aut Atilgan Ali Faculty of Engineering and Natural Sciences, Sabanci University, 34956, Tuzla, Istanbul, Turkey aut Atilgan Canan Faculty of Engineering and Natural Sciences, Sabanci University, 34956, Tuzla, Istanbul, Turkey aut JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/4(2015-06-01), 705-718 0949-8257 20:4<705 2015 20 775 https://doi.org/10.1007/s00775-015-1256-4 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00775-015-1256-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Abdizadeh Haleh Faculty of Engineering and Natural Sciences, Sabanci University, 34956, Tuzla, Istanbul, Turkey aut NATIONALLICENCE 700 1- Atilgan Ali Faculty of Engineering and Natural Sciences, Sabanci University, 34956, Tuzla, Istanbul, Turkey aut NATIONALLICENCE 700 1- Atilgan Canan Faculty of Engineering and Natural Sciences, Sabanci University, 34956, Tuzla, Istanbul, Turkey aut NATIONALLICENCE 773 0- JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/4(2015-06-01), 705-718 0949-8257 20:4<705 2015 20 775