Identification of human liver mitochondrial aldehyde dehydrogenase as a potential target for microcystin-LR.
Microcystins (MCs) are hepatotoxins produced by a variety of freshwater cyanobacteria. The toxicity of these hepatotoxins is a severe health issue for both humans and livestock; MCs have been implicated in the development of liver cancer, necrosis, and even deadly intrahepatic bleeding. Microcystin-LR (MC-LR) is the MC variant most commonly encountered in a contaminated aquatic system. Thus far, MC-LR has only been shown to target the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A) and it is still unknown whether MC-LR can bind and inhibit any other protein targets inside the cell. To find potential MC-LR targets, we screened a phage display library for peptide ligands that specifically recognize MC-LR. Using these peptide sequences as guides, we performed a series of bioinformatics analyses revealing that MC-LR binds human liver aldehyde dehydrogenase 2 (ALDH2) at residues 447-451. We confirmed MC-LR binding of ALDH2 via automated docking computation, which yielded results matching our experimental and bioinformatics analyses. ALDH2 dysfunction may lead to aldehyde-induced reactive oxygen species (ROS) generation and, in turn, apoptosis. Therefore, ALDH2 could potentially be a target of MC-LR associated with the process of ROS-induced apoptosis. Our current study presents a new approach to the study of interactions of biological molecules by combining phage display technology with computational methods.
Chen
Ting
T
State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, Nanjing University, Nanjing 210093, China.
Cui
Jun
J
Liang
Yan
Y
Xin
Xiaoban
X
Owen Young
D
D
Chen
Chun
C
Shen
Pingping
P
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D000458:Cyanobacteria; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006801:Humans; D008024:Ligands; D008387:Marine Toxins; D052998:Microcystins; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000737:chemistry / Q000633:toxicity*; D011485:Protein Binding; D016415:Sequence Alignment; D013045:Species Specificity
D004791:Enzyme Inhibitors; D008024:Ligands; D008387:Marine Toxins; D052998:Microcystins; D019151:Peptide Library; D010456:Peptides, Cyclic; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C057862:cyanoginosin LR