The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional.
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.
Parkash
Vimal
V
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Lindholm
Päivi
P
Peränen
Johan
J
Kalkkinen
Nisse
N
Oksanen
Esko
E
Saarma
Mart
M
Leppänen
Veli-Matti
VM
Goldman
Adrian
A
D018360:Crystallography, X-Ray; D004220:Disulfides / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D009414:Nerve Growth Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D049231:Saposins / Q000378:metabolism; D016415:Sequence Alignment; D013312:Stress, Physiological
C522217:CDNF protein, human; D004220:Disulfides; C099695:MANF protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D049231:Saposins