Abstract
Prostate apoptosis response-4 (Par-4) is a 38 kDa largely intrinsically disordered tumor suppressor protein that functions in cancer cell apoptosis. Par-4 down-regulation is often observed in cancer while up-regulation is characteristic of neurodegenerative conditions such as Alzheimer’s disease. Cleavage of Par-4 by caspase-3 activates tumor suppression via formation of an approximately 25 kDa fragment (cl-Par-4) that enters the nucleus and inhibits Bcl-2 and NF-ƙB, which function in pro-survival pathways. Here, we have investigated the structure of cl-Par-4 using biophysical techniques including circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and intrinsic tyrosine fluorescence. The results demonstrate pH-dependent folding of cl-Par-4, with high disorder and aggregation at neutral pH, but a largely folded, non-aggregated conformation at acidic pH.
Highlights
Prostate apoptosis response-4 (Par-4) is a pro-apoptotic tumor suppressor protein that was first identified in studies of prostate cancer [1,2,3]
The Par-4/PAWR gene is found on the unstable chromosome 12q21.2, which is often mutated or deleted in cancers such as gastric and pancreatic [11]
The most well characterized mode of cancer cell apoptosis induced by extracellular Par-4 is mediated via interaction of Par-4 with the cell surface GRP78 protein [4]
Summary
Par-4 is a pro-apoptotic tumor suppressor protein that was first identified in studies of prostate cancer [1,2,3]. The most well characterized mode of cancer cell apoptosis induced by extracellular Par-4 is mediated via interaction of Par-4 with the cell surface GRP78 protein [4]. This interaction initiates the apoptotic Fas/FasL-FADD caspase-8 pro-death pathway [4,12,13]. Healthy cells have low cell surface levels of GRP78, providing resistance to extracellular Par-4-induced apoptosis [4,14]. Par-4 can induce cancer cell apoptosis intracellularly via nuclear translocation of a C-terminal fragment, as discussed further below [10,15,16]
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