Abstract
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.
Highlights
An understanding of the structure of the C5 variant of human BChE is an extension of the groundbreaking achievement of Joel Sussman and Israel Silman in 1991, when they solved the crystal structure of acetylcholinesterase [1]
We propose that the unknown protein in C5 and cord BChE is encoded by the last exon of the RAPH1 gene
We propose that the instability of C5 is explained by proteolytic cleavage of the long lamellipodin second agar gel [15]
Summary
An understanding of the structure of the C5 variant of human BChE is an extension of the groundbreaking achievement of Joel Sussman and Israel Silman in 1991, when they solved the crystal structure of acetylcholinesterase [1]. This pioneering work in collaboration with Jean. Massoulié contributed to an understanding of the role of proline-rich peptides in assembly of the acetylcholinesterase tetramer [2] It inspired the solution of the human BChE crystal structure [3]. Forty residues at the C-terminus of each BChE subunit constitute the tetramerization domain
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