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J Mol Evol
2016 May 01;824-5:183-98. doi: 10.1007/s00239-016-9732-1.
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Evolution of the α-Subunit of Na/K-ATPase from Paramecium to Homo sapiens: Invariance of Transmembrane Helix Topology.
Morrill GA
,
Kostellow AB
,
Liu L
,
Gupta RK
,
Askari A
.
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Na/K-ATPase is a key plasma membrane enzyme involved in cell signaling, volume regulation, and maintenance of electrochemical gradients. The α-subunit, central to these functions, belongs to a large family of P-type ATPases. Differences in transmembrane (TM) helix topology, sequence homology, helix-helix contacts, cell signaling, and protein domains of Na/K-ATPase α-subunit were compared in fungi (Beauveria), unicellular organisms (Paramecia), primitive multicellular organisms (Hydra), and vertebrates (Xenopus, Homo sapiens), and correlated with evolution of physiological functions in the α-subunit. All α-subunits are of similar length, with groupings of four and six helices in the N- and C-terminal regions, respectively. Minimal homology was seen for protein domain patterns in Paramecium and Hydra, with high correlation between Hydra and vertebrates. Paramecium α-subunits display extensive disorder, with minimal helix contacts. Increases in helix contacts in Hydra approached vertebrates. Protein motifs known to be associated with membrane lipid rafts and cell signaling reveal significant positional shifts between Paramecium and Hydra vulgaris, indicating that regional membrane fluidity changes occur during evolution. Putative steroid binding sites overlapping TM-3 occurred in all species. Sites associated with G-protein-receptor stimulation occur both in vertebrates and amphibia but not in Hydra or Paramecia. The C-terminus moiety "KETYY," necessary for the Na(+) activation of pump phosphorylation, is not present in unicellular species indicating the absence of classical Na(+)/K(+)-pumps. The basic protein topology evolved earliest, followed by increases in protein domains and ordered helical arrays, correlated with appearance of α-subunit regions known to involve cell signaling, membrane recycling, and ion channel formation.
Fig. 1. A comparison of the topology of TM helices of Na/K-ATPase α-subunits of Homo
sapiens (top, #P05023), Hydra vulgaris (middle, #P35317), and Paramecium tetraurelia (bottom, Q6BGF7) using the MemBrain algorithm. The abscissa represents the sequence positions; the ordinate indicates the propensity of TM helices. Plots were obtained as described in âMethodsâ section
Fig. 2. A comparison of the domain topology of the Na/K-ATPase α-subunits from Homo
sapiens (top), Hydra vulgaris (middle), and Paramecium tetraurelia (PARTE, bottom) using the DomPred server (see âMethodsâ section). The vertical peaks and bars indicate the positions of domains within the peptide sequence. The ordinate represents the aligned termini profile and predicts the probability of the respective domains based on the DomPred algorithm
Fig. 3. Comparisons of the contact maps based on the top L/5 predictions for ATP1A1 of Homo sapiens (top), Hydra vulgaris (middle), and Paramecium tetraurelia (bottom). Plots were obtained as described in âMethodsâ section
Fig. 4. A comparison of four MEMPACK-SVM defined TM helices (TM-1âTM-4) in the N-terminal regions of α-subunits of Homo sapiens (top graphic, P05023), Hydra vulgaris (middle graphic, P35317), and Paramecium tetraurelia (bottom graphic, Q6BGF7). Colors in the MEMPACK cartoon indicate hydrophobic residues (blue), polar residues (red), and charged residues (green for negative, purple for positive). Lines between residues indicate predicted helixâhelix interactions
Fig. 5. A comparison of six MEMPACK-SVM defined TM helices (TM-5âTM-10) in the C-terminal region of α-subunits of Homo sapiens (top graphic, P05023), Hydra vulgaris (middle graphic, P35317), Paramecium tetraurelia (bottom graphic, Q6BGF7). Predicted TM helices are indicated in black. Blue squares indicate predicted pore-lining regions. Extracellular regions (membrane loops) are in orange. See âMethodsâ section for details
Fig. 6. Comparisons of the topology of TM helices, disordered regions, and pore-lining regions of Na/K-ATPase α-subunit of Homo
sapiens (upper plot), Hydra vulgaris (middle plot), and Paramecium
tetraurelia (lower plot). Blue squares indicate predicted pore-lining regions and black squares, non-pore helix regions. Predicted TM helices are indicated in black. Blue squares indicate predicted pore-lining regions. Extracellular regions (membrane loops) are in orange. Disordered regions are indicated as open boxes outlined in either red (disordered) or green (Disordered protein binding). See âMethodsâ section for details
Fig. 7. Comparisons of the topology of TM helices (top graphic), protein domains (middle graphic), and disordered and pore-lining regions (lower graphic) of the Na/K-ATPase α-subunit of Beauveria bassiana (strain ARSEF 2860, White Muscardine disease fungus, #J5JMV7). Blue squares indicate predicted pore-lining regions and black squares, non-pore helix regions. Predicted TM helices are indicated in black. Blue squares indicate predicted pore-lining regions. Extracellular regions (membrane loops) are in orange. Disordered regions are indicated as open boxes outlined in either red (Disordered) or green (Disordered protein binding). See Methods for details
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