title: The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers.
abstract: 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.
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil.
authors.forename: Cristiane
authors.initials: C
authors.lastname: Latge
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil.
authors.forename: Katia M S
authors.initials: KM
authors.lastname: Cabral
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil.
authors.forename: Guilherme A P
authors.initials: GA
authors.lastname: de Oliveira
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil.
authors.forename: Diana P
authors.initials: DP
authors.lastname: Raymundo
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Freitas
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil.
authors.forename: Laizes
authors.initials: L
authors.lastname: Johanson
authors.affiliation: the UFRJ/Pólo Xerém, Universidade Federal do Rio de Janeiro 25245-390, Rio de Janeiro, Brazil.
authors.forename: Luciana F
authors.initials: LF
authors.lastname: Romão
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil.
authors.forename: Fernando L
authors.initials: FL
authors.lastname: Palhano
authors.affiliation: the Institut des Sciences Analytiques, UMR 5280 CNRS, 5 rue de la Doua, 69100 Villeurbanne, France, and.
authors.forename: Torsten
authors.initials: T
authors.lastname: Herrmann
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil, the Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil.
authors.forename: Marcius S
authors.initials: MS
authors.lastname: Almeida
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil, foguel@bioqmed.ufrj.br.
authors.forename: Debora
authors.initials: D
authors.lastname: Foguel
mesh_terms: D000818:Animals; D001704:Biopolymers / Q000378:metabolism*; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors / Q000737:chemistry* / Q000502:physiology*; D018696:Neuroprotective Agents; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D001704:Biopolymers; C522217:CDNF protein, human; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D051844:alpha-Synuclein
keywords: Parkinson disease; neurodegeneration; neurotrophic factor; protein dynamic; protein structure; α-synuclein (a-synuclein)