4BIT

solution structure of cerebral dopamine neurotrophic factor (CDNF)

Summary for 4BIT

• Entry DOI: 10.2210/pdb4bit/pdb
• NMR Information: BMRB: 19164
• Descriptor: CEREBRAL DOPAMINE NEUROTROPHIC FACTOR (1 entity in total)
• Functional Keywords: signaling protein, parkinson
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Secreted : Q49AH0
• Total number of polymer chains: 1
• Total formula weight: 18354.34

Authors

Latge, C.,Cabral, K.M.S.,Raymundo, D.P.,Foguel, D.,Herrmann, T.,Almeida, M.S. (deposition date: 2013-04-13, release date: 2014-04-23, Last modification date: 2024-10-16)

Primary citation

Latge, C.,Cabral, K.M.S.,De Oliveira, G.A.P.,Raymundo, D.P.,Freitas, J.A.,Johanson, L.,Romao, L.F.,Palhano, F.L.,Herrmann, T.,Almeida, M.S.,Foguel, D.
The Solution Structure and Dynamics of Full-Length Human Cerebral Dopamine Neurotrophic Factor and its Neuroprotective Role Against Alpha-Synuclein Oligomers.
J.Biol.Chem., 290:20527-20540, 2015

PubMed 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.

PubMed: 26149686
DOI: 10.1074/JBC.M115.662254

Experimental method

SOLUTION NMR