title: The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional.
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.
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Vimal
authors.initials: V
authors.lastname: Parkash
authors.forename: Päivi
authors.initials: P
authors.lastname: Lindholm
authors.forename: Johan
authors.initials: J
authors.lastname: Peränen
authors.forename: Nisse
authors.initials: N
authors.lastname: Kalkkinen
authors.forename: Esko
authors.initials: E
authors.lastname: Oksanen
authors.forename: Mart
authors.initials: M
authors.lastname: Saarma
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Leppänen
authors.forename: Adrian
authors.initials: A
authors.lastname: Goldman
mesh_terms: 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
chemical_list: C522217:CDNF protein, human; D004220:Disulfides; C099695:MANF protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D049231:Saposins