2W51

Human mesencephalic astrocyte-derived neurotrophic factor (MANF)

Summary for 2W51

• Entry DOI: 10.2210/pdb2w51/pdb
• Related: 2W50
• Descriptor: PROTEIN ARMET (1 entity in total)
• Functional Keywords: manf, cdnf, saposin, secreted, er stress, phosphoprotein, neurotrophic factor, sialic acid, glycoprotein, growth factor, hormone
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 18195.14

Authors

Parkash, V.,Lindholm, P.,Peranen, J.,Kalkkinen, N.,Oksanen, E.,Saarma, M.,Leppanen, V.M.,Goldman, A. (deposition date: 2008-12-03, release date: 2009-03-17, Last modification date: 2024-05-01)

Primary citation

Parkash, V.,Lindholm, P.,Peranen, J.,Kalkkinen, N.,Oksanen, E.,Saarma, M.,Leppanen, V.M.,Goldman, A.
The Structure of the Conserved Neurotrophic Factors Manf and Cdnf Explains Why They are Bifunctional.
Protein Eng.Des.Sel., 22:233-241, 2009

PubMed 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.

PubMed: 19258449
DOI: 10.1093/PROTEIN/GZN080

Experimental method

X-RAY DIFFRACTION (2.8 Å)