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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 RMSF of the [AChET]4–ColQ Complex as Calculated from the 100 Lowest Frequency ModesAll residues are numbered continuously (chain A: 1–583, B: 584-1166, C: 1167–1749, D: 1750–2332, ColQ: 2333–2379).
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pcbi-0010062-g002: The RMSF of the [AChET]4–ColQ Complex as Calculated from the 100 Lowest Frequency ModesAll residues are numbered continuously (chain A: 1–583, B: 584-1166, C: 1167–1749, D: 1750–2332, ColQ: 2333–2379).

Mentions: A simplified BNMA was done to calculate the low-frequency modes, using the [AChET]4–ColQ structure model. The first 100 lowest frequency normal modes were obtained. These normal modes are sufficient to capture all the collective motions, and motions with higher frequency are usually localized to a small domain [21,25]. Figure 2 shows the root mean square fluctuations (RMSFs) derived from Equation 1. It appears that the largest structural fluctuations are located at the WAT and PRAD sequences. This is consistent with the fact that these sequences in the two crystal structures (1C2O and 1C2B) of the AChE tetramer were disordered. As can be seen in the correlation map of motions discussed below, the motion experienced by this region is rigid-body in nature. Therefore it does not contradict our hypothesis that WAT and PRAD have very high affinity. Other regions showing high fluctuation are residues 380 to 390 and residues 265 to 276. They are both loops connecting α helices. Residues 380 and 390 are located at the interface between the catalytic domain of AChE and ColQ; therefore the large fluctuation indicates that there is no strong association between them at this region.


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

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

The RMSF of the [AChET]4–ColQ Complex as Calculated from the 100 Lowest Frequency ModesAll residues are numbered continuously (chain A: 1–583, B: 584-1166, C: 1167–1749, D: 1750–2332, ColQ: 2333–2379).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0010062-g002: The RMSF of the [AChET]4–ColQ Complex as Calculated from the 100 Lowest Frequency ModesAll residues are numbered continuously (chain A: 1–583, B: 584-1166, C: 1167–1749, D: 1750–2332, ColQ: 2333–2379).
Mentions: A simplified BNMA was done to calculate the low-frequency modes, using the [AChET]4–ColQ structure model. The first 100 lowest frequency normal modes were obtained. These normal modes are sufficient to capture all the collective motions, and motions with higher frequency are usually localized to a small domain [21,25]. Figure 2 shows the root mean square fluctuations (RMSFs) derived from Equation 1. It appears that the largest structural fluctuations are located at the WAT and PRAD sequences. This is consistent with the fact that these sequences in the two crystal structures (1C2O and 1C2B) of the AChE tetramer were disordered. As can be seen in the correlation map of motions discussed below, the motion experienced by this region is rigid-body in nature. Therefore it does not contradict our hypothesis that WAT and PRAD have very high affinity. Other regions showing high fluctuation are residues 380 to 390 and residues 265 to 276. They are both loops connecting α helices. Residues 380 and 390 are located at the interface between the catalytic domain of AChE and ColQ; therefore the large fluctuation indicates that there is no strong association between them at this region.

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