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Article Dans Une Revue Journal of Biological Chemistry Année : 2015

The solution structure and dynamics of full-length human cerebral dopamine neurotrophic factor and its neuroprotective role against α-synuclein oligomers

Résumé

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.

Dates et versions

hal-01187615 , version 1 (27-08-2015)

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Citer

Cristiane Latge, Katia M. S. Cabral, Guilherme A. P. de Oliveira, Diana P. Raymundo, Julia A. Freitas, et al.. The solution structure and dynamics of full-length human cerebral dopamine neurotrophic factor and its neuroprotective role against α-synuclein oligomers. Journal of Biological Chemistry, 2015, 290 (33), pp.20527-20540. ⟨10.1074/jbc.M115.662254⟩. ⟨hal-01187615⟩
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