Journal of Biological Chemistry
Volume 290, Issue 33, 14 August 2015, Pages 20527-20540
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Protein Structure and Folding
The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers*

https://doi.org/10.1074/jbc.M115.662254Get rights and content
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Cerebral dopamine neurotrophic factor (CDNF) is a promising therapeutic agent for Parkinson disease. As such, there has been great interest in studying its mode of action, which remains unknown. The three-dimensional crystal structure of the N terminus (residues 9–107) of CDNF has been determined, but there have been no published structural studies on the full-length protein due to proteolysis of its C-terminal domain, which is considered intrinsically disordered. An improved purification protocol enabled us to obtain active full-length CDNF and to determine its three-dimensional structure in solution. CDNF contains two well folded domains (residues 10–100 and 111–157) that are linked by a loop of intermediate flexibility. We identified two surface patches on the N-terminal domain that were characterized by increased conformational dynamics that should allow them to embrace active sites. One of these patches is formed by residues Ser-33, Leu-34, Ala-66, Lys-68, Ile-69, Leu-70, Ser-71, and Glu-72. The other includes a flexibly disordered N-terminal tail (residues 1–9), followed by the N-terminal portion of α-helix 1 (residues Cys-11, Glu-12, Val-13, Lys-15, and Glu-16) and residue Glu-88. The surface of the C-terminal domain contains two conserved active sites, which have previously been identified in mesencephalic astrocyte-derived neurotrophic factor, a CDNF paralog, which corresponds to its intracellular mode of action. We also showed that CDNF was able to protect dopaminergic neurons against injury caused by α-synuclein oligomers. This advises its use against physiological damages caused by α-synuclein oligomers, as observed in Parkinson disease and several other neurodegenerative diseases.

α-synuclein (a-synuclein)
neurodegeneration
neurotrophic factor
Parkinson disease
protein dynamic
protein structure

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The atomic coordinates and structure factors (code 4BIT) have been deposited in the Protein Data Bank (http://wwpdb.org/).

The 1H, 13C, and 15N chemical shifts of CDNF have been deposited in the BioMagResBank (71) under BMRB code 19164.

*

This work was supported by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro and Conselho Nacional de Desenvolvimento Científico e Tecnológico Grants Universal 470349/2012-3, APQ1/E-26/111.771/2012 (to M. S. A.) and Universal 442991/2014-2, APQ1/E-26/111.415/2013 (to F. L. P.). The authors declare that they have no conflicts of interest with the contents of this article.