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Abnormal processing of an autism‐linked Arg to Cys mutation in proteins of the α/β hydrolase fold family
Author(s) -
De Jaco Antonella,
Comoletti Davide,
Kovarik Zrinka,
Gaietta Guido,
Radic Zoran,
Lockridge Oksana,
Ellisman Mark H.,
Taylor Palmer
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a502-e
Subject(s) - butyrylcholinesterase , lactacystin , acetylcholinesterase , endoplasmic reticulum , hydrolase , proteasome , biochemistry , mutation , chemistry , wild type , hek 293 cells , biology , microbiology and biotechnology , mutant , enzyme , proteasome inhibitor , aché , gene
A mutation linked to autism encodes an Arg to Cys replacement in the C‐terminal portion of the extracellular domain of neuroligin‐3 (NL‐3). The exposed Cys causes retention of the protein in the endoplasmic reticulum (ER) when expressed in HEK‐293 cells. An homologous Arg to Cys substitution was reported for butyrylcholinesterase (BuChE) in patients with post‐succinylcholine apnea. NL3, BuChE, and acetylcholinesterase (AChE) are members of the α/β hydrolase fold family of proteins sharing common tertiary structures. Despite the distinct oligomeric assemblies and cellular dispositions, Arg residues in NL‐3 (Arg451), in BuChE (Arg386) and in AChE (Arg395) are conserved in mammalian α/β hydrolase fold proteins. Introducing the Arg to Cys mutation in the c‐DNA of AChE and BuChE we find that the homologous Arg to Cys substitution also results in ER retention of the cholinesterase enzymes. Treatment with the proteasome inhibitor lactacystin showed that all three proteins are degraded via the proteasome pathway. In particular, lactacystin treatment has a more pronounced effect on the mutated proteins suggesting that they are degraded to a greater extent of the wild type protein. (supported by R37‐GM 18360 to PT and 5R01NS014718‐21, 2P41RR004050‐16 to MHE, NAAR #843 to DC).