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
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...
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MDPI AG
2022-04-01
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author | Ehsan Sarafraz-Yazdi Stephen Mumin Diana Cheung Daniel Fridman Brian Lin Lawrence Wong Ramon Rosal Rebecca Rudolph Matthew Frenkel Anusha Thadi William F. Morano Wilbur B. Bowne Matthew R. Pincus Josef Michl |
author_facet | Ehsan Sarafraz-Yazdi Stephen Mumin Diana Cheung Daniel Fridman Brian Lin Lawrence Wong Ramon Rosal Rebecca Rudolph Matthew Frenkel Anusha Thadi William F. Morano Wilbur B. Bowne Matthew R. Pincus Josef Michl |
author_sort | Ehsan Sarafraz-Yazdi |
collection | DOAJ |
description | 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. |
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issn | 2227-9059 |
language | English |
last_indexed | 2024-03-10T03:18:17Z |
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spelling | doaj.art-42c0ab7d56654ac4b1d38423cc4eef802023-11-23T10:08:49ZengMDPI AGBiomedicines2227-90592022-04-0110594510.3390/biomedicines10050945PNC-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 LysisEhsan Sarafraz-Yazdi0Stephen Mumin1Diana Cheung2Daniel Fridman3Brian Lin4Lawrence Wong5Ramon Rosal6Rebecca Rudolph7Matthew Frenkel8Anusha Thadi9William F. Morano10Wilbur B. Bowne11Matthew R. Pincus12Josef Michl13NomoCan Pharmaceuticals LLC, New York Blood Center, 310 East 67th Street, New York, NY 10065, USANomoCan Pharmaceuticals LLC, New York Blood Center, 310 East 67th Street, New York, NY 10065, USADepartment of Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USADepartment of Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USADepartment of Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USADepartment of Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USADepartment of Health of New York City, 455 First Avenune, New York, NY 10016, USAMicroscopy and Imaging Department, American Museum of Natural History, Central Park West and 79th Street, New York, NY 10024, USAMicroscopy and Imaging Department, American Museum of Natural History, Central Park West and 79th Street, New York, NY 10024, USADepartment of Surgery, Drexel University College of Medicine, 230 North Broad Street, Philadelphia, PA 19102, USADepartment of Surgery, Drexel University College of Medicine, 230 North Broad Street, Philadelphia, PA 19102, USADepartment of Surgery, Drexel University College of Medicine, 230 North Broad Street, Philadelphia, PA 19102, USADepartment of Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USADepartment of Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USAPNC-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.https://www.mdpi.com/2227-9059/10/5/945PNC-27p53 binding domaincell-penetrating peptides (CPP)HDM-2/MDM-2plasma membrane pore formation |
spellingShingle | Ehsan Sarafraz-Yazdi Stephen Mumin Diana Cheung Daniel Fridman Brian Lin Lawrence Wong Ramon Rosal Rebecca Rudolph Matthew Frenkel Anusha Thadi William F. Morano Wilbur B. Bowne Matthew R. Pincus Josef Michl 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 Biomedicines PNC-27 p53 binding domain cell-penetrating peptides (CPP) HDM-2/MDM-2 plasma membrane pore formation |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | PNC-27 p53 binding domain cell-penetrating peptides (CPP) HDM-2/MDM-2 plasma membrane pore formation |
url | https://www.mdpi.com/2227-9059/10/5/945 |
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