caa a22 4500 445321482 CHVBK 20180317142705.0 cr unu---uuuuu 170323e20110601xx s 000 0 eng 10.1007/s10534-011-9410-0 doi (NATIONALLICENCE)springer-10.1007/s10534-011-9410-0 In silico modeling of the Menkes copper-translocating P-type ATPase 3rd metal binding domain predicts that phosphorylation regulates copper-binding [Elektronische Daten] [N. Veldhuis, M. Kuiper, R. Dobson, R. Pearson, J. Camakaris] The Menkes (ATP7A) P1B-type ATPase is a transmembrane copper-translocating protein. It contains six similar high-affinity metal-binding domains (MBDs) in the N-terminal cytoplasmic tail that are important for sensing intracellular copper and regulating ATPase function through the transfer of copper between domains. Molecular characterization of copper-binding and transfer is predominantly dependent on NMR structures derived from E. coli expression systems. A limitation of these models is the exclusion of post-translational modifications. We have previously shown that the third copper-binding domain, MBD3, uniquely contains two phosphorylated residues: Thr-327, which is phosphorylated only in the presence of elevated copper; and Ser-339, which is constitutively phosphorylated independent of copper levels. Here, using molecular dynamic simulations, we have incorporated these phosphorylated residues into a model based on the NMR structures of MBD3. Our data suggests that constitutively phosphorylated Ser-339, which is in a loop facing the copper-binding site, may facilitate the copper transfer process by exposing the CxxC copper-binding region of MBD3. Copper-induced phosphorylation of Thr327 is predicted to stabilize this change in conformation. This offers new molecular insights into how cell signaling (phosphorylation) can affect MBD structure and dynamics and how this may in turn affect copper-binding and thus copper-translocation functions of ATP7A. Springer Science+Business Media, LLC., 2011 Menkes copper-translocating P-type ATPase nationallicence ATP7A nationallicence Metal-binding domain 3 nationallicence Molecular dynamics nationallicence Phosphorylation nationallicence Veldhuis N. Department of Pharmacology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut Kuiper M. Victorian Partnership of Advanced Computing, 3053, Carlton, VIC, Australia aut Dobson R. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, 3010, Melbourne, VIC, Australia aut Pearson R. Peter MacCallum Cancer Centre, 3000, East Melbourne, VIC, Australia aut Camakaris J. Department of Genetics, The University of Melbourne, 3010, Melbourne, VIC, Australia aut BioMetals Springer Netherlands 24/3(2011-06-01), 477-487 0966-0844 24:3<477 2011 24 10534 https://doi.org/10.1007/s10534-011-9410-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10534-011-9410-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Veldhuis N. Department of Pharmacology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- Kuiper M. Victorian Partnership of Advanced Computing, 3053, Carlton, VIC, Australia aut NATIONALLICENCE 700 1- Dobson R. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, 3010, Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- Pearson R. Peter MacCallum Cancer Centre, 3000, East Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- Camakaris J. Department of Genetics, The University of Melbourne, 3010, Melbourne, VIC, Australia aut NATIONALLICENCE 773 0- BioMetals Springer Netherlands 24/3(2011-06-01), 477-487 0966-0844 24:3<477 2011 24 10534 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer