Aβ42 facilitates the activation of Discoidin Domain Receptor 2 and Its nuclear enrichment in Alzheimer's Disease Model

Discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase (RTK) family member, plays a pivotal role in collagen-mediated signaling, influencing several key cellular processes. In Alzheimers disease (AD), DDR2 expression and activity are significantly upregulated. While collagens, the endogenous ligands of DDR2, either remain unchanged or are downregulated in AD-like conditions, Amyloid-beta 42 (A{beta}42) has been found to activate DDR2 in the absence of collagen non-canonically. Additionally, DDR2 naturally translocates to the nucleus in the neuroblastoma cell line SH-SY5Y, and the pool of DDR2 increases further in the nucleus in the presence of A{beta}42, suggesting its novel pathological role in AD. The E113K mutant of DDR2, where the collagen-binding site has been compromised, fails to get activated by collagen, whereas A{beta}42 could still activate it. Furthermore, the DDR2 inhibitor WRG-28 effectively inhibits A{beta}42 induced phosphorylation of the protein. We have also modeled in silico the ectodomain of DDR2, extending through the transmembrane helix, and subsequently docked A{beta}42 pentamer to elucidate the mechanistic basis of kinase activation by amyloid A{beta}. Additionally, we analyzed WRG-28 binding by constructing the ternary complex of DDR2, A{beta}42, and WRG-28. Our structural analyses offer key insights into the molecular mechanisms governing DDR2 activation by A{beta}42 and its inhibition by WRG-28 in the AD cell model, providing a foundation for targeted therapeutic strategies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/694181v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1fd0a08org.highwire.dtl.DTLVardef@19db92borg.highwire.dtl.DTLVardef@1e7b7e7org.highwire.dtl.DTLVardef@1dad3fc_HPS_FORMAT_FIGEXP M_FIG C_FIG