Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects neurons and repairs the Parkinson disease-like symptoms in a rat 6-hydroxydopamine model. We show a three-dimensional solution structure of human MANF that differs drastically from other neurotrophic factors. Remarkably, the C-terminal domain of MANF (C-MANF) is homologous to the SAP domain of Ku70, a well known inhibitor of proapoptotic Bax (Bcl-2-associated X protein). Cellular studies confirm that MANF and C-MANF protect neurons intracellularly as efficiently as Ku70.
Highlights
Valently assembled dimer [2]
Mesencephalic astrocyte-derived neurotrophic factor (MANF) [6] and cerebral dopamine neurotrophic factor (CDNF) [7] belong to fourth family of neurotrophic factors
The primary sequence of MANF contains eight conserved cysteines, corresponding to residues Cys6, Cys9, Cys40, Cys51, Cys82, Cys93, Cys127, and Cys130, which according to electrospray-ionization mass spectrometry and crystal structure analysis, all form disulfide bonds in maturated protein [7, 12, 20, 21]
Summary
Valently assembled dimer [2]. Neurotrophins act through two distinct receptors types: tropomyosin-related kinase and low affinity p75 neurotrophin receptor (p75NTR) with a cysteinerich extracellular region [3]. We used NMR spectroscopy to solve a three-dimensional solution structure of full-length MANF (FL-MANF) protein as well as its isolated C-terminal domain (C-MANF) comprising residues 96 –158 (numbered according to mature protein).
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