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

Quantitative analysis on secretion level of CDNF regulated by two key α‐helices in CDNF protein

“…In our previous studies, we have found that the secretion of M1 protein reduced significantly compared with Wt but the secretion of M7 protein showed higher than Wt (Sun et al, ; Liu et al, ). In this study, we constructed fusion plasmids of Wt, M1, and M7 with NanoLuc separately as shown in Figure A.…”

“…In our previous studies, we found α1 and α7 which locate in the N‐terminal and C‐terminal respectively can regulate the intracellular trafficking and secretion of CDNF in PC12 cells. (Sun et al, ; Liu et al, ). α1 mutation led to most CDNF protein retained in the ER and could not traffic to Golgi apparatus, resulting in the reduced secretion.…”

“…There are eight α‐helices in the crystal structure of CDNF protein. By inserting a proline (P) into respective position to destroy the corresponding α‐helix structure in CDNF, we have found two helices which can regulate its intracellular trafficking and secretion (Sun et al, ; Liu et al, ). One is α1 that is located in the N‐terminal saposin‐like domain.…”

“…The other is α7 that is located in the C‐terminal SAP‐domain. Disrupting of α7 can induce most CDNF protein secreting out the cells and little retaining in the cell body (Liu et al, ). These findings have been verified by western blot or immunofluorescence staining.…”

Cerebral Dopamine Neurotrophic Factor: A Potential Therapeutic Agent for Parkinson’s Disease

“…In comparison with the N-terminus, the C-terminus might have a marked effect through the unfolded Cys-Xaa-Xaa-Cys (CXXC) domain and a putative endoplasmic reticulum (ER) retention signal sequence (KTEL), indicating that CDNF might be involved in ER stress, which is an important component of PD pathogenesis [18][19][20][21]. Mutation of the CXXC motif of the C-terminal domain abolishes the actions of MANF and CDNF; in contrast, expression of the C-terminal domain rescues sympathetic neurons from toxin-induced apoptosis in a Drosophila model [22,23]. In PD patients, the C allele of an intronic CDNF single nucleotide polymorphism (rs7094179) has been associated with susceptibility to PD [24].…”