In Silico docking analysis of Amyloid Precursor Protein Intracellular Domain (AICD) with neuronal cytoplasmic and nuclear membrane proteins and its relevance in neuronal death and AD pathogenesis

• Author Details:   
• Jagadeesh Kumar D
• Mainak Mondal
• Kapil Kumar Mehta
• Priya Narayan
• H.G. Nagendra

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Recent evidences reveal the controlled intramembrane proteolysis of the C-terminal fragment of amyloid precursor-protein (APP) by gamma-secretases, yielding an additional 57 residue peptide fragment called APP intracellular domain (AICD). This AICD is known to interact with cytoplasmic and neuronal proteins, and trigger AD pathology. Appreciating the fact that, the key motifs in the c-terminal residues of AICD exhibit strong binding preferences, our study focuses on deciphering the modes of interactions with 16 select cytoplasmic and neuronal proteins via in silico methods. The results suggest that key residues of the AICD belonging to the YENTPY motif interact with most of the 16 functionally important neuronal proteins. Docking studies indicate that the proteins such as Lamin2, GRP78, ABAD, TOM20, TOM70, NUDC, HSPA8, TOG and neuroserpin interact very strongly with the AICD fragment. These computational results provide vital insights into the binding patterns of AICD with these crucial neuronal proteins, thus suggesting design and development of plausible inhibitors that could control the disease progression, neurodegeneration, and neuronal death, which are all potential hall marks of AD.

Keywords: Alzheimer's disease, Amyloid precursor-protein, AICD, Neurodegeneration, Neuronal proteins.