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Protein Eng Des Sel. 2009 Apr;22(4):233-41. doi: 10.1093/protein/gzn080. Epub 2009 Mar 3.

The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional.

Author information

1
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

Abstract

We have solved the structures of mammalian mesencephalic astrocyte-derived neurotrophic factor (MANF) and conserved dopamine neurotrophic factor (CDNF). CDNF protects and repairs midbrain dopaminergic neurons in vivo; MANF supports their survival in culture and is also cytoprotective against endoplasmic reticulum (ER) stress. Neither protein structure resembles any known growth factor but the N-terminal domain is a saposin-like lipid-binding domain. MANF and CDNF may thus bind lipids or membranes. Consistent with this, there are two patches of conserved lysines and arginines. The natively unfolded MANF C-terminus contains a CKGC disulphide bridge, such as reductases and disulphide isomerases, consistent with a role in ER stress response. The structure thus explains why MANF and CDNF are bifunctional; neurotrophic activity may reside in the N-terminal domain and ER stress response in the C-terminal domain. Finally, we identified three changes, (MANF)I10-->K(CDNF), (MANF)E79-->M(CDNF) and (MANF)K88-->L(CDNF), that may account for the biological differences between the proteins.

PMID:
19258449
DOI:
10.1093/protein/gzn080
[Indexed for MEDLINE]

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