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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 Structures Related to AChE Tetramerization(A) The [WAT]4PRAD complex structure. (B) The compact tetramer structure. (C) The loose tetramer structure. (D) The [AChET]4–ColQ complex model constructed according to the [WAT]4PRAD complex structure. Each chain is colored differently (A, blue; B, red; C, gray; D, orange; ColQ, yellow). The catalytic S203 was shown as a green ball model for each AChE subunit, and the cyan surfaces are residues near the peripheral site.
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pcbi-0010062-g001: The Structures Related to AChE Tetramerization(A) The [WAT]4PRAD complex structure. (B) The compact tetramer structure. (C) The loose tetramer structure. (D) The [AChET]4–ColQ complex model constructed according to the [WAT]4PRAD complex structure. Each chain is colored differently (A, blue; B, red; C, gray; D, orange; ColQ, yellow). The catalytic S203 was shown as a green ball model for each AChE subunit, and the cyan surfaces are residues near the peripheral site.

Mentions: Recently the crystal structure of PRAD/WAT complex was solved at 2.35 Å resolution [11]. The complex has the expected [WAT]4PRAD stoichiometry. Four parallel α-helical WAT chains wrap around a single antiparallel PRAD helix, which itself has a left-handed polyproline II conformation. Each WAT helix assumes a coiled-coil conformation, and all four of them form a left-handed supercoil around the PRAD (Figure 1A). The WWW motif in the WAT makes repetitive hydrophobic stacking and hydrogen bond interactions with the PRAD. The four WAT chains are related by a 4-fold screw axis around the PRAD. The strength of PRAD–WAT interaction is very tight, with no monomer of WAT detected in the range of 10−10 to 10−12 M [8].


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

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

The Structures Related to AChE Tetramerization(A) The [WAT]4PRAD complex structure. (B) The compact tetramer structure. (C) The loose tetramer structure. (D) The [AChET]4–ColQ complex model constructed according to the [WAT]4PRAD complex structure. Each chain is colored differently (A, blue; B, red; C, gray; D, orange; ColQ, yellow). The catalytic S203 was shown as a green ball model for each AChE subunit, and the cyan surfaces are residues near the peripheral site.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0010062-g001: The Structures Related to AChE Tetramerization(A) The [WAT]4PRAD complex structure. (B) The compact tetramer structure. (C) The loose tetramer structure. (D) The [AChET]4–ColQ complex model constructed according to the [WAT]4PRAD complex structure. Each chain is colored differently (A, blue; B, red; C, gray; D, orange; ColQ, yellow). The catalytic S203 was shown as a green ball model for each AChE subunit, and the cyan surfaces are residues near the peripheral site.
Mentions: Recently the crystal structure of PRAD/WAT complex was solved at 2.35 Å resolution [11]. The complex has the expected [WAT]4PRAD stoichiometry. Four parallel α-helical WAT chains wrap around a single antiparallel PRAD helix, which itself has a left-handed polyproline II conformation. Each WAT helix assumes a coiled-coil conformation, and all four of them form a left-handed supercoil around the PRAD (Figure 1A). The WWW motif in the WAT makes repetitive hydrophobic stacking and hydrogen bond interactions with the PRAD. The four WAT chains are related by a 4-fold screw axis around the PRAD. The strength of PRAD–WAT interaction is very tight, with no monomer of WAT detected in the range of 10−10 to 10−12 M [8].

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