Structural highlights
Disease
[MANF_HUMAN] Familial pancreatic carcinoma.
Function
[MANF_HUMAN] Selectively promotes the survival of dopaminergic neurons of the ventral mid-brain. Modulates GABAergic transmission to the dopaminergic neurons of the substantia nigra. Enhances spontaneous, as well as evoked, GABAergic inhibitory postsynaptic currents in dopaminergic neurons (By similarity). Inhibits cell proliferation and endoplasmic reticulum (ER) stress-induced cell death.[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional.,Parkash V, Lindholm P, Peranen J, Kalkkinen N, Oksanen E, Saarma M, Leppanen VM, Goldman A Protein Eng Des Sel. 2009 Apr;22(4):233-41. Epub 2009 Mar 3. PMID:19258449[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Petrova P, Raibekas A, Pevsner J, Vigo N, Anafi M, Moore MK, Peaire AE, Shridhar V, Smith DI, Kelly J, Durocher Y, Commissiong JW. MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci. 2003 Apr;20(2):173-88. PMID:12794311
- ↑ Apostolou A, Shen Y, Liang Y, Luo J, Fang S. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Exp Cell Res. 2008 Aug 1;314(13):2454-67. doi: 10.1016/j.yexcr.2008.05.001. Epub , 2008 May 13. PMID:18561914 doi:http://dx.doi.org/10.1016/j.yexcr.2008.05.001
- ↑ Parkash V, Lindholm P, Peranen J, Kalkkinen N, Oksanen E, Saarma M, Leppanen VM, Goldman A. 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. Epub 2009 Mar 3. PMID:19258449 doi:10.1093/protein/gzn080
