The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers

• Published in: The Journal of biological chemistry 2015-08, Vol.290 (33), p.20527-20540
• Main Authors: Latge, Cristiane, Cabral, Katia M.S., de Oliveira, Guilherme A.P., Raymundo, Diana P., Freitas, Julia A., Johanson, Laizes, Romão, Luciana F., Palhano, Fernando L., Herrmann, Torsten, Almeida, Marcius S., Foguel, Debora
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Analytical chemistry; Animals; Biopolymers - metabolism; Cell Line; Chemical Sciences; Crystallography, X-Ray; Humans; Mice; Nerve Growth Factors - chemistry; Nerve Growth Factors - physiology; neurodegeneration; Neuroprotective Agents; neurotrophic factor; Nuclear Magnetic Resonance, Biomolecular; Parkinson disease; Protein Conformation; protein dynamic; protein structure; Protein Structure and Folding; Structure-Activity Relationship; α-synuclein (a-synuclein)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.662254

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. Background: Cerebral dopamine neurotrophic factor (CDNF) is a promising therapeutic agent for treating Parkinson disease. Results: We determined the solution structure of CDNF and demonstrated its neuroprotective effects against insults caused by α-synuclein oligomers. Conclusion: We identified structural features of CDNF that might correspond with its physiological activity. Significance: This work strengthens the therapeutic relevance of using CDNF to treat neurodegenerative diseases.