Journal:Protein Science:3
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<b>Molecular Tour</b><br> | <b>Molecular Tour</b><br> | ||
| - | Metal ions are often involved in catalytic functions in proteins, but may also serve to stabilize them. Thus, ''Torpedo californica'' acetylcholinesterase (''Tc''AChE) is strongly stabilized against thermal denaturation by the divalent cations, Mg<sup>+2</sup>, Mn<sup>+2</sup>, and Ca<sup>+2</sup>. Solution of the crystal structures of the complexes of ''Tc''AChE with Mg<sup>+2</sup> and Ca<sup>+2</sup>. revealed that stabilization is achieved by binding of the divalent metal ions to a cluster of carboxylate groups of four aspartates that has been called a | + | Metal ions are often involved in catalytic functions in proteins, but may also serve to stabilize them. Thus, ''Torpedo californica'' acetylcholinesterase (''Tc''AChE) is strongly stabilized against thermal denaturation by the divalent cations, Mg<sup>+2</sup>, Mn<sup>+2</sup>, and Ca<sup>+2</sup>. Solution of the crystal structures of the complexes of ''Tc''AChE with Mg<sup>+2</sup> and Ca<sup>+2</sup>. revealed that stabilization is achieved by binding of the divalent metal ions to a cluster of carboxylate groups of four aspartates that has been called a 4D motif. The complex contains, in addition, several water molecules, and while the metal ions bind directly to two of the Asp carboxylates, they bind to the other two indirectly, via waters. |
The 4D motif is a novel motif, which has not been described before. The ASSAM server, http://27.126.156.175/assam, which identifies structural motifs in proteins, revealed that many other proteins contain the 4D motif, and in a substantial percentage of them solution of their crystal structures reveals one of the three metal ions referred to above, or also Zn<sup>+2</sup>. Whereas in ''Tc''AChE the 4D motif contains a single divalent ion, together with the waters, in some such complexes two or three metal ions are seen. The 4D motif is thus a versatile motif with respect to the number of ions and waters that it contains. | The 4D motif is a novel motif, which has not been described before. The ASSAM server, http://27.126.156.175/assam, which identifies structural motifs in proteins, revealed that many other proteins contain the 4D motif, and in a substantial percentage of them solution of their crystal structures reveals one of the three metal ions referred to above, or also Zn<sup>+2</sup>. Whereas in ''Tc''AChE the 4D motif contains a single divalent ion, together with the waters, in some such complexes two or three metal ions are seen. The 4D motif is thus a versatile motif with respect to the number of ions and waters that it contains. | ||
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The 4 Asp residues, D326, D389, D392 and D393, are shown as sticks, with carbons in green, oxygens in red, and nitrogens in blue. Solvent waters are shown as blue spheres, and the metal ions as magenta spheres, with their sizes proportionate to their Van der Waals radii; the oxygens of the uranyl moiety are shown as red spheres. Non-covalent hydrogen bonds and ionic bonds are shown as dashed white lines. | The 4 Asp residues, D326, D389, D392 and D393, are shown as sticks, with carbons in green, oxygens in red, and nitrogens in blue. Solvent waters are shown as blue spheres, and the metal ions as magenta spheres, with their sizes proportionate to their Van der Waals radii; the oxygens of the uranyl moiety are shown as red spheres. Non-covalent hydrogen bonds and ionic bonds are shown as dashed white lines. | ||
| - | <scene name='87/876867/Cv/9'>Overall views of the Mg+2/TcAChE complex</scene>. Ribbon diagram of the Mg< | + | <scene name='87/876867/Cv/9'>Overall views of the Mg+2/TcAChE complex</scene>. Ribbon diagram of the Mg<sup>+2</sup>/''Tc''AChE complex. The representation shows the entire structure, with the first sub-domain, residues 4-305 in cyan, and the second, residues 306-535, in red. It is oriented looking into the active-site gorge, with W279, in the peripheral anionic site (PAS), at the top of the gorge, and W84, in the catalytic anionic site (CAS) towards the back, adjacent to the catalytic triad, S200-E327-H440. All these residues are depicted as sticks. The long α-helix, N383-K413, against which the D4 pocket is glued, is in magenta, and the two helices that contribute to the 4-helix bundle of the dimer, D365-Y375 and V518-T535, are in yellow. The Mg<sup>+2</sup> in the 4D pocket is in blue, and is surrounded by 4 waters in grey. A conserved water H-bonds with D326, of the 4D motif, with E327 and H440, in the catalytic triad, and with the main-chain nitrogen of F330, which, in turn, contributes to the CAS. This water which is homologous to water 623 in Koellner ''et al''<ref name="Koellner">PMID:10669619</ref>, is shown as an orange sphere. <scene name='87/876867/Cv/10'>Close up, with the same orientation</scene>, showing the interactions of the active site, the D4 pocket, and the conserved water, shown as an orange sphere. |
| - | [[Image:Fig_07.jpg|thumb|400px|left|'''Fig. 7.''' Sequence alignments of residues 320-400 in several AChEs and in hBChE. The numbering used is that of ''Tc''AChE. Fully conserved residues are in white on a red background. The columns for the four residues corresponding to the | + | [[Image:Fig_07.jpg|thumb|400px|left|'''Fig. 7.''' Sequence alignments of residues 320-400 in several AChEs and in hBChE. The numbering used is that of ''Tc''AChE. Fully conserved residues are in white on a red background. The columns for the four residues corresponding to the 4D motif in ''Tc''AChE and zebrafish acetylcholinesterase are framed in green, and it can be seen that the motif is conserved only in these three AChEs. ''Tc''AChE, ''Torpedo californica'' AChE; ''Tm''AChE, ''Torpedo marmorata'' AChE; ''Ee''AChE, ''Electrophorus electricus'' AChE; ''Dr''AChE, ''Danio rerio'' AChE; ''Bf''AChE, ''Bungarus fasciatus'' AChE; HuAChE, human AChE; BoAChE, bovine AChE; MoAChE, mouse AChE; HdAChE, designed HuAChE, D4 variant<ref name="Goldenzweig">PMID:27425410</ref>; HuBChE, human BChE; ''Ag''AChE, ''Anopheles gambiae'' AChE; ''Dm''AChE, ''Drosophila melanogaster'' AChE.]] |
Pocket in ''Bf''AChE that is homologous to the 4D pocket in ''Tc''AChE: | Pocket in ''Bf''AChE that is homologous to the 4D pocket in ''Tc''AChE: | ||
Revision as of 15:25, 10 March 2021
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This page complements a publication in scientific journals and is one of the Proteopedia's Interactive 3D Complement pages. For aditional details please see I3DC.
