Rescue and Stabilization of Acetylcholinesterase in Skeletal Muscle by N-terminal Peptides Derived from the Noncatalytic Subunits

Ruiz, Carlos A.; Rossi, Susana G.; Rotundo, Richard L.

doi:10.1074/jbc.m115.653741

Cited by 6 publications

(4 citation statements)

References 41 publications

(11 reference statements)

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“…The polyproline-rich peptides in wild-type human BChE range in size from 21 to 32 residues [ 4 , 5 ] and derive from lamellipodin (Q70E73; RAPH1 gene). Studies with recombinant human BChE have demonstrated that BChE monomers can assemble into tetramers by addition of either short polyproline peptides (17–50 Pro residues) or long polyproline peptides with an average mass of 30,000 Da [ 6 ], in agreement with initial observations with recombinant AChE [ 7 , 8 ] and confirmed in skeletal muscle AChE [ 9 ].…”

Section: Introductionsupporting

confidence: 79%

The C5 Variant of the Butyrylcholinesterase Tetramer Includes a Noncovalently Bound 60 kDa Lamellipodin Fragment

et al. 2017

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Humans with the C5 genetic variant of butyrylcholinesterase (BChE) have 30–200% higher plasma BChE activity, low body weight, and shorter duration of action of the muscle relaxant succinylcholine. The C5 variant has an extra, slow-moving band of BChE activity on native polyacrylamide gel electrophoresis. This band is about 60 kDa larger than wild-type BChE. Umbilical cord BChE in 100% of newborn babies has a C5-like band. Our goal was to identify the unknown, 60 kDa protein in C5. Both wild-type and C5 BChE are under the genetic control of two independent loci, the BCHE gene on Chr 3q26.1 and the RAPH1 (lamellipodin) gene on Chr 2q33. Wild-type BChE tetramers are assembled around a 3 kDa polyproline peptide from lamellipodin. Western blot of boiled C5 and cord BChE showed a positive response with an antibody to the C-terminus of lamellipodin. The C-terminal exon of lamellipodin is about 60 kDa including an N-terminal polyproline. We propose that the unknown protein in C5 and cord BChE is encoded by the last exon of the RAPH1 gene. In 90% of the population, the 60 kDa fragment is shortened to 3 kDa during maturation to adulthood, leaving only 10% of adults with C5 BChE.

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Section: Introductionsupporting

confidence: 79%

The C5 Variant of the Butyrylcholinesterase Tetramer Includes a Noncovalently Bound 60 kDa Lamellipodin Fragment

et al. 2017

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“…) and there is now clear evidence that the AChE molecules in this pool can at least in part be rescued and rerouted to the cell surface in culture and to the synapses in vivo (Ruiz et al . , and unpublished observations).…”

Section: Early Events In the Biogenesis Of Achementioning

confidence: 55%

“…These studies also suggest a therapeutic application of the PRAD peptides since a synthetic PRAD‐KDEL peptide can be taken up by cells where it rescues the inactive AChE from degradation (Ruiz et al . ). This ability to increase AChE could be useful in the treatment of patients suffering from nerve agent or pesticide exposure.…”

Section: Discussionmentioning

confidence: 97%

“…When tissue cultured muscle cells are incubated with a proline‐rich attachment domain (PRAD) peptide synthesized with a KDEL endoplasmic reticulum retention sequence on the carboxyl terminus the peptide is taken up and retrogradely transported to the site of AChE assembly (Ruiz et al . ). This in turn results in a large increase in catalytically active AChE, up to 400%, as a consequence of stabilization of the inactive AChE molecules.…”

Section: Role Of the Non‐catalytic Subunits In Ache Assembly; Prad Anmentioning

confidence: 97%

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Biogenesis, assembly and trafficking of acetylcholinesterase

Rotundo

2017

Journal of Neurochemistry

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Acetylcholinesterase (AChE) is expressed as several homomeric and hetero-oligomeric forms in a wide variety of tissues such as neurons in the central and peripheral nervous systems and their targets including skeletal muscle, endocrine and exocrine glands. In addition, glycolipid-anchored forms are expressed in erythropoietic and lymphopoietic cells. While transcriptional and post-transcriptional regulation is important for determining which AChE oligomeric forms are expressed in a given tissue, translational and post-translational regulatory mechanisms at the level of protein folding, assembly and sorting play equally important roles in assuring that the AChE molecules reach their intended sites on the cell surface in the appropriate numbers. This brief review will focus on the latter events in the cell with the goal of providing novel therapeutic interventional strategies for the treatment of organophosphate and carbamate pesticide and nerve agent exposure.

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Polyproline-rich peptides associated with Torpedo californica acetylcholinesterase tetramers

Toker

Silman

Zeev‐Ben‐Mordehai

et al. 2020

Chemico-Biological Interactions

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Rescue and Stabilization of Acetylcholinesterase in Skeletal Muscle by N-terminal Peptides Derived from the Noncatalytic Subunits

Cited by 6 publications

References 41 publications

The C5 Variant of the Butyrylcholinesterase Tetramer Includes a Noncovalently Bound 60 kDa Lamellipodin Fragment

The C5 Variant of the Butyrylcholinesterase Tetramer Includes a Noncovalently Bound 60 kDa Lamellipodin Fragment

Biogenesis, assembly and trafficking of acetylcholinesterase

Polyproline-rich peptides associated with Torpedo californica acetylcholinesterase tetramers

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