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

J Biol Chem. 2015 Aug 14;290(33):20527-40. doi: 10.1074/jbc.M115.662254. Epub 2015 Jul 6.


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.

Keywords: Parkinson disease; neurodegeneration; neurotrophic factor; protein dynamic; protein structure; α-synuclein (a-synuclein).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopolymers / metabolism*
  • Cell Line
  • Crystallography, X-Ray
  • Humans
  • Mice
  • Nerve Growth Factors / chemistry*
  • Nerve Growth Factors / physiology*
  • Neuroprotective Agents*
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Conformation
  • Structure-Activity Relationship
  • alpha-Synuclein / metabolism*


  • Biopolymers
  • CDNF protein, human
  • Nerve Growth Factors
  • Neuroprotective Agents
  • alpha-Synuclein

Associated data

  • PDB/1JJR
  • PDB/2KVD
  • PDB/2W50
  • PDB/2W51
  • PDB/4BIT