Journal:Protein Science:4

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Revision as of 17:46, 18 November 2024

Why is binding of a divalent metal cation to a structural motif containing four carboxylate residues not accompanied by a conformational change?

Lushchekina, Weiner, Ashani, Emrizal, Firdaus-Raih, Silman & Sussman^[1]

Molecular Tour

For a divalent cation, it is hard to unbind from structural motifs composed of 4 acidic residues (4A). However, it is much easier if the motif is surrounded by 3 basic residues (4A/3B).

Torpedo californica acetylcholinesterase (TcAChE) contains a unique 4D motif composed of four aspartate residues that can bind divalent metal cations (like Ca²⁺, Mg²⁺, Mn²⁺), significantly increasing the enzyme’s thermal stability. Despite the electrostatic repulsion expected between these aspartates, structural analysis shows that the enzyme's conformation remains stable

or bound cations as seen in an the two states and an between them. The stability of the 4D motif is attributed to adjacent positively charged residues (Lys325, Arg388, and Arg517), forming stabilizing salt bridges, leading to the newly named (four acidic residues stabilized by three basic residues).

The study also identified additional metal-binding sites (His264 and His471 sites) in TcAChE through crystallographic analysis, but these appear to be weaker or crystallographic artifacts. Using metadynamics and molecular dynamics (MD) simulations with quantum potentials (QM/MM-MD), the binding strength of metal cations at the 4D site was compared to that of the 4D site in human fibrin-stabilizing factor (fXIIIa), which lacks stabilizing cationic residues. Results showed that while TcAChE’s 4A/3B motif maintains structural integrity upon metal binding/unbinding, the is stable in presence of a metal ion but without a metal ions due to electrostatic repulsion. This is seen clearly in an between these two states.

The 4A/3B motif’s metal-binding strength is weaker (~10 kcal/mol) compared to motifs with multiple anionic residues not surrounded by cationic residues. This flexibility without conformational change suggests the motif may act as a metal ion reservoir, potentially regulating metal concentrations or adapting thermal stability. Similar motifs were found in other proteins, indicating a broader functional role beyond TcAChE.

References

↑ Lushchekina S, Weiner L, Ashani Y, Emrizal R, Firdaus-Raih M, Silman I, Sussman JL. Why is binding of a divalent metal cation to a structural motif containing four carboxylate residues not accompanied by a conformational change? Protein Sci. 2024 Dec;33(12):e5206. PMID:39548604 doi:10.1002/pro.5206

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Joel L. Sussman, Jaime Prilusky

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.

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@@ Line 5: / Line 5: @@
 <hr/>
 <b>Molecular Tour</b><br>
-[[Image:2024_Lushchekina_Prot_Sci_x.jpg| thumb |left|250px|For a divalent cation, it is quite hard to unbind from structural motifs composed of 4 acidic residues (4A). However, it is much easier in motifs where three surrounding basic residues form ion pairs with three carboxylates (4A/3B), and not undergo a conformational change upon binding or unbinding the divalent cation.]]''Torpedo californica'' acetylcholinesterase (''Tc''AChE) contains a unique 4D motif composed of four aspartate residues that can bind divalent metal cations (like Ca²⁺, Mg²⁺, Mn²⁺), significantly increasing the enzyme’s thermal stability. Despite the electrostatic repulsion expected between these aspartates, structural analysis shows that the enzyme's conformation remains stable
+[[Image:2024_Lushchekina_Prot_Sci_x.jpg| thumb |left|250px|For a divalent cation, it is hard to unbind from structural motifs composed of 4 acidic residues (4A). However, it is much easier if the motif is surrounded by 3 basic residues  (4A/3B).]]''Torpedo californica'' acetylcholinesterase (''Tc''AChE) contains a unique 4D motif composed of four aspartate residues that can bind divalent metal cations (like Ca²⁺, Mg²⁺, Mn²⁺), significantly increasing the enzyme’s thermal stability. Despite the electrostatic repulsion expected between these aspartates, structural analysis shows that the enzyme's conformation remains stable
 <scene name='10/1063617/009_fig_metal_tcache_lab_png/2'>with</scene> or <scene name='10/1063617/009_fig_apo_tcache_lab_png/2'>without</scene> bound cations as seen in an <scene name='10/1063617/009_fig_metal_apo_tcache_lab/2'>overlay</scene> the two states and an <jmol>
 <jmolButton>

Journal:Protein Science:4

From Proteopedia

Revision as of 17:46, 18 November 2024

Why is binding of a divalent metal cation to a structural motif containing four carboxylate residues not accompanied by a conformational change?

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