HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 14, 9667-9676, April 7, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/14/9667    most recent M510262200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by De Jaco, A. Articles by Taylor, P. Search for Related Content PubMed PubMed Citation Articles by De Jaco, A. Articles by Taylor, P. Social Bookmarking                      What's this?

A Mutation Linked with Autism Reveals a Common Mechanism of Endoplasmic Reticulum Retention for the ,-Hydrolase Fold Protein Family^*

Antonella De Jaco, Davide Comoletti, Zrinka Kovarik¹, Guido Gaietta, Zoran Radi, Oksana Lockridge^¶, Mark H. Ellisman, and Palmer Taylor²

From the Departments of Pharmacology and Neurosciences and National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, California 92093-0636 and ^¶Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805

A mutation linked to autistic spectrum disorders encodes an Arg to Cys replacement in the C-terminal portion of the extracellular domain of neuroligin-3. The solvent-exposed Cys causes virtually complete retention of the protein in the endoplasmic reticulum when the protein is expressed in transfected cells. An identical Cys substitution was reported for butyrylcholinesterase through genotyping patients with post-succinylcholine apnea. Neuroligin, butyrylcholinesterase, and acetylcholinesterase are members of the ,-hydrolase fold family of proteins sharing sequence similarity and common tertiary structures. Although these proteins have distinct oligomeric assemblies and cellular dispositions, homologous Arg residues in neuroligin-3 (Arg-451), in butyrylcholinesterase (Arg-386), and in acetylcholinesterase (Arg-395) are conserved in all studied mammalian species. To examine whether an homologous Arg to Cys mutation affects related proteins similarly despite their differing capacities to oligomerize, we inserted homologous mutations in the acetylcholinesterase and butyrylcholinesterase cDNAs. Using confocal fluorescence microscopy and analysis of oligosaccharide processing, we find that the homologous Arg to Cys mutation also results in endoplasmic reticulum retention of the two cholinesterases. Small quantities of mutated acetylcholinesterase exported from the cell retain activity but show a greater K_m, a much smaller k_cat, and altered substrate inhibition. The nascent proteins associate with chaperones during processing, but the mutation presumably restricts processing through the endoplasmic reticulum and Golgi apparatus, because of local protein misfolding and inability to oligomerize. The mutation may alter the capacity of these proteins to dissociate from their chaperone prior to oligomerization and processing for export.

Received for publication, September 19, 2005 , and in revised form, January 10, 2006.

^* This work was supported by the Rotary Foundation Ambassadorial Scholar Fellowship (to A. D. J.), National Alliance for Autism Research Grant 843 (to D. C.), National Institutes of Health, Division of Research Resources grant (to M. H. E.), and United States Public Health Service Grants R37-GM18360 and P42-ES 10337 (to P. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Institute for Medical Research and Occupational Health, P. O. 291, HR-10001 Zagreb, Croatia.

² To whom correspondence should be addressed: Dept. of Pharmacology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0636. Tel.: 858-534-1366; Fax: 858-534-8248; E-mail: pwtaylor{at}ucsd.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. N. Hebert and M. Molinari In and Out of the ER: Protein Folding, Quality Control, Degradation, and Related Human Diseases Physiol Rev, October 1, 2007; 87(4): 1377 - 1408. [Abstract] [Full Text] [PDF]