4bit | pdb_00004bit
solution structure of cerebral dopamine neurotrophic factor (CDNF)
Structural highlights
Function[CDNF_HUMAN] Trophic factor for dopamine neurons. Prevents the 6-hydroxydopamine (6-OHDA)-induced degeneration of dopaminergic neurons. When administered after 6-OHDA-lesioning, restores the dopaminergic function and prevents the degeneration of dopaminergic neurons in substantia nigra (By similarity). Publication Abstract from PubMedCerebral Dopamine Neurotrophic Factor (CDNF) is a promising therapeutic agent for Parkinson's disease. As such, there has been great interest in studying its mode of action, which remains unknown. The 3D 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 3D structure in solution. CDNF contains two well-folded domains (residues 10100 and 111157) 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 S33, L34, A66, K68, I69, L70, S71 and E72. The other includes a flexibly disordered N-terminal tail (residues 19), followed by the N-terminal portion of alpha-helix 1 (residues C11, E12, V13, K15 and E16) and residue E88. 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 alpha-synuclein oligomers. This advises its use against physiological damages caused by alpha-synuclein oligomers, as observed in Parkinson's disease and several other neurodegenerative diseases. The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role Against alpha-Synuclein Oligomers.,Latge C, Cabral KM, de Oliveira GA, Raymundo DP, Freitas JA, Johanson L, Romao LF, Palhano FL, Herrmann T, Almeida MS, Foguel D J Biol Chem. 2015 Jul 6. pii: jbc.M115.662254. PMID:26149686[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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