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• W2890102390 abstract "Bcl-2 family proteins play a crucial role in regulating apoptosis, a process critical for development, eliminating damaged or infected cells, host-pathogen interactions and in disease. Dysregulation of Bcl-2 proteins elicits an expansive cell survival mechanism promoting cell migration, invasion and metastasis. Through a network of intra-family protein-protein interactions Bcl-2 family members regulate the release of cell death factors from mitochondria. NRZ is a novel zebrafish pro-survival Bcl-2 orthologue resident on mitochondria and the endoplasmic reticulum (ER). However, the mechanism of NRZ apoptosis inhibition has not yet been clarified. Here we examined the interactions of NRZ with pro-apoptotic members of the Bcl-2 family using a combination of isothermal calorimetry and mutational analysis of NRZ. We show that NRZ binds almost all zebrafish pro-apoptotic proteins and displays a broad range of affinities. Furthermore, we define the structural basis for apoptosis inhibition of NRZ by solving the crystal structure of both apo-NRZ and a holo form bound to a peptide spanning the binding motif of the pro-apoptotic zBad, a BH3-only protein orthologous to mammalian Bad. The crystal structure of NRZ revealed that it adopts the conserved Bcl-2 like fold observed for other cellular pro-survival Bcl-2 proteins and employs the canonical ligand binding groove to bind Bad BH3 peptide. NRZ engagement of Bad BH3 involves the canonical ionic interaction between NRZ R86 and Bad D104 and an additional ionic interaction between NRZ D79 and Bad R100, and substitution of either NRZ R86 or D79 to Ala reduces the binding to Bad BH3 tenfold or more. Our findings provide a detailed mechanistic understanding for NRZ mediated anti-apoptotic activity in zebrafish by revealing binding to both Bad and Noxa, suggesting that NRZ is likely to occupy a unique mechanistic role in zebrafish apoptosis regulation by acting as a highly promiscuous pro-apoptotic Bcl-2 binder." @default.
• W2890102390 created "2018-09-27" @default.
• W2890102390 creator A5015605647 @default.
• W2890102390 creator A5065738535 @default.
• W2890102390 creator A5066995121 @default.
• W2890102390 creator A5084768069 @default.
• W2890102390 creator A5086689325 @default.
• W2890102390 date "2018-09-20" @default.
• W2890102390 modified "2023-10-12" @default.
• W2890102390 title "A structural investigation of NRZ mediated apoptosis regulation in zebrafish" @default.
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• W2890102390 doi "https://doi.org/10.1038/s41419-018-0992-0" @default.
• W2890102390 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6148235" @default.
• W2890102390 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30237469" @default.
• W2890102390 hasPublicationYear "2018" @default.
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