PNC-27, a Chimeric p53-Penetratin Peptide Binds to HDM-2 in a p53 Peptide-like Structure, Induces Selective Membrane-Pore Formation and Leads to Cancer Cell Lysis
Name
biomedicines-10-00945.pdf
Size
2.98 MB
Format
Unknown
Checksum (MD5)
0b2ea21fd285e6e2684fa60d371d7376
Author(s)
Sarafraz-Yazdi, Ehsan
Mumin, Stephen
Cheung, Diana
Fridman, Daniel
Lin, Brian
Wong, Lawrence
Rosal, Ramon
Rudolph, Rebecca
Frenkel, Matthew
Thadi, Anusha
Date Issued
April 2022
Journal
Biomedicines
Publisher
MDPI AG
Citation
Biomedicines 10 (5): 945 (2022)
Version
Final published version
Abstract
PNC-27, a 32-residue peptide that contains an HDM-2 binding domain and a cell-penetrating peptide (CPP) leader sequence kills cancer, but not normal, cells by binding to HDM-2 associated with the plasma membrane and induces the formation of pores causing tumor cell lysis and necrosis. Conformational energy calculations on the structure of PNC-27 bound to HDM-2 suggest that 1:1 complexes form between PNC-27 and HDM-2 with the leader sequence pointing away from the complex. Immuno-scanning electron microscopy was carried out with cancer cells treated with PNC-27 and decorated with an anti-PNC-27 antibody coupled to 6 nm gold particles and an anti-HDM-2 antibody linked to 15 nm gold particles. We found multiple 6 nm- and 15 nm-labeled gold particles in approximately 1:1 ratios in layered ring-shaped structures in the pores near the cell surface suggesting that these complexes are important to the pore structure. No pores formed in the control, PNC-27-treated untransformed fibroblasts. Based on the theoretical and immuno-EM studies, we propose that the pores are lined by PNC-27 bound to HDM-2 at the membrane surface with the PNC-27 leader sequence lining the pores or by PNC-27 bound to HDM-2.
Terms of Use
Creative Commons Attribution
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.3390/biomedicines10050945
