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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Disulfides / metabolism
  • Humans
  • Lipid Metabolism
  • Nerve Growth Factors / chemistry*
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Protein Folding
  • Saposins / metabolism
  • Sequence Alignment
  • Stress, Physiological


  • CDNF protein, human
  • Disulfides
  • MANF protein, human
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Saposins