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The association of tetrameric acetylcholinesterase with ColQ tail: a block normal mode analysis.

Zhang D, McCammon JA - PLoS Comput. Biol. (2005)

Bottom Line: The structure was optimized using energy minimization.Normal mode involvement analysis revealed that the two lowest frequency modes were primarily involved in the conformational changes leading to the two crystal structures.The first 30 normal modes can account for more than 75% of the conformational changes in both cases.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, University of California, San Diego, California, USA. dzhang@mccammon.ucsd.edu

ABSTRACT
Acetylcholinesterase (AChE) rapidly hydrolyzes acetylcholine in the neuromuscular junctions and other cholinergic synapses to terminate the neuronal signal. In physiological conditions, AChE exists as tetramers associated with the proline-rich attachment domain (PRAD) of either collagen-like Q subunit (ColQ) or proline-rich membrane-anchoring protein. Crystallographic studies have revealed that different tetramer forms may be present, and it is not clear whether one or both are relevant under physiological conditions. Recently, the crystal structure of the tryptophan amphiphilic tetramerization (WAT) domain of AChE associated with PRAD ([WAT]4PRAD), which mimics the interface between ColQ and AChE tetramer, became available. In this study we built a complete tetrameric mouse [AChE(T)]4-ColQ atomic structure model, based on the crystal structure of the [WAT]4PRAD complex. The structure was optimized using energy minimization. Block normal mode analysis was done to investigate the low-frequency motions of the complex and to correlate the structure model with the two known crystal structures of AChE tetramer. Significant low-frequency motions among the catalytic domains of the four AChE subunits were observed, while the [WAT]4PRAD part held the complex together. Normal mode involvement analysis revealed that the two lowest frequency modes were primarily involved in the conformational changes leading to the two crystal structures. The first 30 normal modes can account for more than 75% of the conformational changes in both cases. The evidence further supports the idea of a flexible tetramer model for AChE. This model can be used to study the implications of the association of AChE with ColQ.

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The Involvement Analysis of the Low-Frequency Modes of the [AChET]4–ColQ ComplexThe involvement of the modes was shown for the conformational change to (A) the compact and (B) loose tetramer structures. The cumulative involvement of the modes was shown for (C) the compact and (D) loose tetramer structures.
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pcbi-0010062-g004: The Involvement Analysis of the Low-Frequency Modes of the [AChET]4–ColQ ComplexThe involvement of the modes was shown for the conformational change to (A) the compact and (B) loose tetramer structures. The cumulative involvement of the modes was shown for (C) the compact and (D) loose tetramer structures.

Mentions: Figure 4 shows the results for the involvement analysis of these conformational changes. In the case of the compact tetramer, the lowest frequency mode (except the trivial modes corresponding to translation and rotation) has the highest coefficient at 0.53 as seen in Figure 4A. Such a large involvement coefficient indicates that this mode is highly relevant to the conformational change from the symmetric model to the compact tetramer structure. Figure 5A illustrates the collective motions in this mode by plotting the displacement onto each residue. The frequency of this mode is 1.39 cm−1. It seems that in this mode the subunits move closer to each other, as the inter-subunit distance is shorter in the compact tetramer structure compared to the symmetric model of [AChET]4–ColQ complex. The cumulative involvement plot in Figure 4C shows that the first 30 lowest frequency modes can account for 80% of the motions in the conformational change to the compact tetramer structure.


The association of tetrameric acetylcholinesterase with ColQ tail: a block normal mode analysis.

Zhang D, McCammon JA - PLoS Comput. Biol. (2005)

The Involvement Analysis of the Low-Frequency Modes of the [AChET]4–ColQ ComplexThe involvement of the modes was shown for the conformational change to (A) the compact and (B) loose tetramer structures. The cumulative involvement of the modes was shown for (C) the compact and (D) loose tetramer structures.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1285061&req=5

pcbi-0010062-g004: The Involvement Analysis of the Low-Frequency Modes of the [AChET]4–ColQ ComplexThe involvement of the modes was shown for the conformational change to (A) the compact and (B) loose tetramer structures. The cumulative involvement of the modes was shown for (C) the compact and (D) loose tetramer structures.
Mentions: Figure 4 shows the results for the involvement analysis of these conformational changes. In the case of the compact tetramer, the lowest frequency mode (except the trivial modes corresponding to translation and rotation) has the highest coefficient at 0.53 as seen in Figure 4A. Such a large involvement coefficient indicates that this mode is highly relevant to the conformational change from the symmetric model to the compact tetramer structure. Figure 5A illustrates the collective motions in this mode by plotting the displacement onto each residue. The frequency of this mode is 1.39 cm−1. It seems that in this mode the subunits move closer to each other, as the inter-subunit distance is shorter in the compact tetramer structure compared to the symmetric model of [AChET]4–ColQ complex. The cumulative involvement plot in Figure 4C shows that the first 30 lowest frequency modes can account for 80% of the motions in the conformational change to the compact tetramer structure.

Bottom Line: The structure was optimized using energy minimization.Normal mode involvement analysis revealed that the two lowest frequency modes were primarily involved in the conformational changes leading to the two crystal structures.The first 30 normal modes can account for more than 75% of the conformational changes in both cases.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, University of California, San Diego, California, USA. dzhang@mccammon.ucsd.edu

ABSTRACT
Acetylcholinesterase (AChE) rapidly hydrolyzes acetylcholine in the neuromuscular junctions and other cholinergic synapses to terminate the neuronal signal. In physiological conditions, AChE exists as tetramers associated with the proline-rich attachment domain (PRAD) of either collagen-like Q subunit (ColQ) or proline-rich membrane-anchoring protein. Crystallographic studies have revealed that different tetramer forms may be present, and it is not clear whether one or both are relevant under physiological conditions. Recently, the crystal structure of the tryptophan amphiphilic tetramerization (WAT) domain of AChE associated with PRAD ([WAT]4PRAD), which mimics the interface between ColQ and AChE tetramer, became available. In this study we built a complete tetrameric mouse [AChE(T)]4-ColQ atomic structure model, based on the crystal structure of the [WAT]4PRAD complex. The structure was optimized using energy minimization. Block normal mode analysis was done to investigate the low-frequency motions of the complex and to correlate the structure model with the two known crystal structures of AChE tetramer. Significant low-frequency motions among the catalytic domains of the four AChE subunits were observed, while the [WAT]4PRAD part held the complex together. Normal mode involvement analysis revealed that the two lowest frequency modes were primarily involved in the conformational changes leading to the two crystal structures. The first 30 normal modes can account for more than 75% of the conformational changes in both cases. The evidence further supports the idea of a flexible tetramer model for AChE. This model can be used to study the implications of the association of AChE with ColQ.

Show MeSH
Related in: MedlinePlus