Key subdomains in the C-terminal of cerebral dopamine neurotrophic factor regulate the protein secretion

Cerebral dopamine neurotrophic factor (CDNF) is a novel evolutionary conserved neurotrophic factor (NTF) which can protect and repairs dopamine neurons in animal models of Parkinson's disease. The crystal structure of CDNF is dominated by eight α-helices and the 3-dimensional structure of CDNF consists of an N-terminal saposin-like domain and a C-terminal SAP-domain. In particular, the C-terminal domain contains two critical motifs, a CXXC motif and a putative ER retention signal sequences (KTEL) at the C-terminus, which indicate that CDNF may be involved in endoplasmic reticulum (ER) stress. In this study, we found that disrupting helix-7 in the C-terminal could significantly increase CDNF secretion. Moreover, we identified the 149aa-154aa is the key amino acids in helix-7. In all, these findings suggest that helix-7 in the C-terminal is important for CDNF secretion, which maybe potential affect CDNF function in ER stress.