pH-Induced Folding of the Caspase-Cleaved Par-4 Tumor Suppressor: Evidence of Structure Outside of the Coiled Coil Domain

• Published in: Biomolecules (Basel, Switzerland) Vol. 8; no. 4; p. 162
• Main Authors: Clark, Andrea M, Ponniah, Komala, Warden, Meghan S, Raitt, Emily M, Yawn, Andrea C, Pascal, Steven M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.12.2018; MDPI
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Apoptosis; Apoptosis Regulatory Proteins - chemistry; Apoptosis Regulatory Proteins - genetics; Bcl-2 protein; Biophysical Phenomena; Cancer; Caspase 3 - chemistry; Caspase 3 - genetics; Caspase-3; Cell Nucleus - chemistry; Cell Nucleus - genetics; Circular Dichroism; coiled coil (CC), leucine zipper (LZ), apoptosis; Dynamic Light Scattering; Fluorescence; Genes, Tumor Suppressor; Humans; Hydrogen-Ion Concentration; intrinsically disordered protein (IDP); Light scattering; Localization; Molecular weight; Neurodegenerative diseases; NF-kappa B - genetics; pH effects; Prostate; Prostate apoptosis response 4 protein; prostate apoptosis response-4 (Par-4); Protein Aggregation, Pathological - genetics; Protein Domains - genetics; Protein expression; Protein Folding; Proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Spectroscopy; Spectrum analysis; Tumor suppressor genes; Tyrosine; Tyrosine - chemistry; United States > US; coiled coil (CC), leucine zipper (LZ), apoptosis; cancer; circular dichroism; intrinsically disordered protein (IDP); prostate apoptosis response-4 (Par-4)
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom8040162

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.