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Glial cell line-derived neurotrophic factor: Characterization of mammalian posttranslational modifications.
MedLine Citation:
PMID:  23305235     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Introduction. Although glial cell line-derived neurotrophic factor (GDNF) has a strong clinical potential, little is known of how the posttranslational modifications of GDNF affect its biological activity and therapeutic potential. In mammalian cells GDNF is synthesized as a preproprotein. During secretion GDNF dimerizes, folds with -S-S- bonds, is modified by N-linked glycosylation, and undergoes proteolytic processing. After production in E. coli, unglycosylated GDNF is renaturated in vitro. Nevertheless, GDNF from E. coli was used in Parkinson's disease-related clinical trials. Material and methods. Constructs encoding variants of human GDNF were generated and expressed in mammalian cells. The proteins were analysed by SDS-PAGE, Western blotting, RET-phosphorylation assays, and N-terminal sequencing. The stability of mammalian GDNF was compared to commercial GDNF produced in E. coli. Results. Posttranslational processing of mammalian GDNF depends on the expression conditions. Two forms of GDNF with different N-termini are formed. GDNF without a prosequence is secreted and biologically active. GDNF is modified by N-linked glycosylation at one (Asn(49)) out of two consensus sites. N-linked glycosylation aids proteolytic processing of GDNF. Both glycosylated and unglycosylated GDNF from mammalian cells are more stable than GDNF from E. coli. Discussion. Posttranslational modifications of GDNF influence its stability, which may be critical for its clinical use.
Authors:
Elisa Piccinini; Nisse Kalkkinen; Mart Saarma; Pia Runeberg-Roos
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Publication Detail:
Type:  Journal Article     Date:  2012-03-09
Journal Detail:
Title:  Annals of medicine     Volume:  45     ISSN:  1365-2060     ISO Abbreviation:  Ann. Med.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8906388     Medline TA:  Ann Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  66-73     Citation Subset:  IM    
Affiliation:
Institute of Biotechnology, University of Helsinki , PB 56 (Viikinkaari 9), SF-00014, University of Helsinki , Finland.
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