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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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Related in: MedlinePlus

The Motion Correlation Map of the [AChET]4–ColQ Complex as Predicted by BNMAOnly one AChE subunit and ColQ were plotted here (AChE: 1–583, ColQ: 584–630).
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pcbi-0010062-g003: The Motion Correlation Map of the [AChET]4–ColQ Complex as Predicted by BNMAOnly one AChE subunit and ColQ were plotted here (AChE: 1–583, ColQ: 584–630).

Mentions: The correlation map can identify collective motions, which are often important large-scale motions related to the protein's biological function. Due to the large amount of data, only one AChET subunit and the ColQ are presented in the motion correlation map in Figure 3. The WAT domain, which corresponds to residues 544 to 583 in Figure 3, has little or no correlation with the catalytic domain of AChE. Instead, it moves together with ColQ (residues 584 to 630), as implied by the high correlation between the WAT and ColQ. This further demonstrates that the interaction between AChE and ColQ is weak, and the interaction between WAT and ColQ is strong. An interesting region in the correlation map can be found for residues 355 to 410. These residues form an α helix bundle themselves and are isolated in the correlation map from the rest of the catalytic domain of AChE. Therefore it appears that these residues form a subdomain. Structurally, Pro410 breaks this subdomain from a long helix, and Ser355 is connected to a flexible loop. They can be considered as hinges connecting different domains. We note that Pro410 is almost universally conserved in all cholinesterases. In our [AChET]4–ColQ complex model, this subdomain makes contact with the C-terminal extension of ColQ, as is evident from the correlation map. In addition, this subdomain participates in the inter-subunit interface with the clockwise neighboring subunit.


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

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

The Motion Correlation Map of the [AChET]4–ColQ Complex as Predicted by BNMAOnly one AChE subunit and ColQ were plotted here (AChE: 1–583, ColQ: 584–630).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0010062-g003: The Motion Correlation Map of the [AChET]4–ColQ Complex as Predicted by BNMAOnly one AChE subunit and ColQ were plotted here (AChE: 1–583, ColQ: 584–630).
Mentions: The correlation map can identify collective motions, which are often important large-scale motions related to the protein's biological function. Due to the large amount of data, only one AChET subunit and the ColQ are presented in the motion correlation map in Figure 3. The WAT domain, which corresponds to residues 544 to 583 in Figure 3, has little or no correlation with the catalytic domain of AChE. Instead, it moves together with ColQ (residues 584 to 630), as implied by the high correlation between the WAT and ColQ. This further demonstrates that the interaction between AChE and ColQ is weak, and the interaction between WAT and ColQ is strong. An interesting region in the correlation map can be found for residues 355 to 410. These residues form an α helix bundle themselves and are isolated in the correlation map from the rest of the catalytic domain of AChE. Therefore it appears that these residues form a subdomain. Structurally, Pro410 breaks this subdomain from a long helix, and Ser355 is connected to a flexible loop. They can be considered as hinges connecting different domains. We note that Pro410 is almost universally conserved in all cholinesterases. In our [AChET]4–ColQ complex model, this subdomain makes contact with the C-terminal extension of ColQ, as is evident from the correlation map. In addition, this subdomain participates in the inter-subunit interface with the clockwise neighboring subunit.

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