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PEDS Advance Access published online on March 3, 2009
Protein Engineering Design and Selection, doi:10.1093/protein/gzn080
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

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

Vimal Parkash1,4, Päivi Lindholm1,4, Johan Peränen1, Nisse Kalkkinen1, Esko Oksanen1, Mart Saarma1, Veli-Matti Leppänen1,3 and Adrian Goldman1,2,5

1 Institute of Biotechnology 2 Neuroscience Center, University of Helsinki, Helsinki, Finland

5 To whom correspondence should be addressed. E-mail: adrian.goldman{at}helsinki.fi

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, MANFI10->KCDNF, MANFE79->MCDNF and MANFK88->LCDNF, that may account for the biological differences between the proteins.

Keywords: ER stress/MANF and CDNF/natively unfolded protein/neurotrophic factor/saposin

Received November 27, 2008; revised November 27, 2008; accepted December 1, 2008.

3 Present address: Molecular Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

4 These authors contributed equally to this work.


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