Journal Article

PUBDB-2024-07265

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural basis of CDNF interaction with the UPR regulator GRP78

Graewert, M. A.EMBL* ; Volkova, M. ; Jonasson, K. ; Määttä, J. A. E. ; Gräwert, T. ; Mamidi, S. ; Kulesskaya, N. ; Evenäs, J. ; Johnsson, R. E. ; Svergun, D.EMBL* ; Bhattacharjee, A. (Corresponding author) ; Huttunen, H. J. (Corresponding author)

2024
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-024-52478-0  doi:10.3204/PUBDB-2024-07265

Abstract: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that is a disease-modifying drug candidate for Parkinson’s disease. CDNF has pleiotropic protective effects on stressed cells, but its mechanism of action remains incompletely understood. Here, we use state-of-the-art advanced structural techniques to resolve the structural basis of CDNF interaction with GRP78, the master regulator of the unfolded protein response (UPR) pathway. Subsequent binding studies confirm the obtained structural model of the complex, eventually revealing the interaction site of CDNF and GRP78. Finally, mutating the key residues of CDNF mediating its interaction with GRP78 not only results in impaired binding of CDNF but also abolishes the neuroprotective activity of CDNF-derived peptides in mesencephalic neuron cultures. These results suggest that the molecular interaction with GRP78 mediates the neuroprotective actions of CDNF and provide a structural basis for development of next generation CDNF-based therapeutic compounds against neurodegenerative diseases.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)
2. EMBL (EMBL)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. iNEXT-Discovery - Infrastructure for transnational access and discovery in structural biology (871037) (871037)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2024

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