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. 2023 Mar 7;20(2):20220049.
doi: 10.1515/jib-2022-0049. eCollection 2023 Jun 1.

Study of NAD-interacting proteins highlights the extent of NAD regulatory roles in the cell and its potential as a therapeutic target

Sara Duarte-Pereira  1   2 , Sérgio Matos  1   3 , José Luís Oliveira  1   3 , Raquel M Silva  2   4
Affiliations

Study of NAD-interacting proteins highlights the extent of NAD regulatory roles in the cell and its potential as a therapeutic target

Sara Duarte-Pereira et al. J Integr Bioinform. .

Abstract

Nicotinamide adenine dinucleotide (NAD) levels are essential for the normal physiology of the cell and are strictly regulated to prevent pathological conditions. NAD functions as a coenzyme in redox reactions, as a substrate of regulatory proteins, and as a mediator of protein-protein interactions. The main objectives of this study were to identify the NAD-binding and NAD-interacting proteins, and to uncover novel proteins and functions that could be regulated by this metabolite. It was considered if cancer-associated proteins were potential therapeutic targets. Using multiple experimental databases, we defined datasets of proteins that directly interact with NAD - the NAD-binding proteins (NADBPs) dataset - and of proteins that interact with NADBPs - the NAD-protein-protein interactions (NAD-PPIs) dataset. Pathway enrichment analysis revealed that NADBPs participate in several metabolic pathways, while NAD-PPIs are mostly involved in signalling pathways. These include disease-related pathways, namely, three major neurodegenerative disorders: Alzheimer's disease, Huntington's disease, and Parkinson's disease. Then, the complete human proteome was further analysed to select potential NADBPs. TRPC3 and isoforms of diacylglycerol (DAG) kinases, which are involved in calcium signalling, were identified as new NADBPs. Potential therapeutic targets that interact with NAD were identified, that have regulatory and signalling functions in cancer and neurodegenerative diseases.

Keywords: NAD metabolism; cancer; interactome; neurodegenerative disorders; signalling.

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Figures

Figure 1:
Figure 1:
Venn-diagram showing the number of NAD-binding proteins obtained from each source.
Figure 2:
Figure 2:
Classification of the NAD-binding proteins according to the protein class from PANTHER (www.pantherdb.org). The graphics represent the classes with more than 10 proteins. The remaining 43 classes comprising a total of 105 proteins are under the label “other” and 71 proteins remained non-classified.
Figure 3:
Figure 3:
Venn-diagram representing the protein-protein interactions from STRING, BIOGRID and IMEX databases, where the 439 NADBPs were used as query.
Figure 4:
Figure 4:
Protein–protein interactions of NUDIX proteins from the NAD-binding proteins dataset. (a) NUDT7 and (b) NUDT12. Queried proteins are represented by red nodes and the line thickness indicates the confidence level of the interaction. Only physical interactions are represented. The network was obtained through STRING (string-db.org).
Figure 5:
Figure 5:
Docking results for NAD ligand on TRPC3 as a target (D6RC49 and J3QTB0). Protein 3D structures were obtained from AlphaFold (https://alphafold.ebi.ac.uk/) and visualized using Pymol software.
See this image and copyright information in PMC

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