The Combinatorial PP1-Binding Consensus Motif (R/K)x (0,1)V/IxFxx(R/K)x(R/K) Is a New Apoptotic Signature

PLoS One

Julien Guergnon¹  Alphonse Garcia¹  Angélique N. Godet¹  Virginie Maire¹  Amélie Croset¹ 

[1] Laboratoire E3 Phosphatases, Unité Signalisation Moléculaire et Activation Cellulaire, Institut Pasteur, Paris, France

关键词: Sequence motif analysis;    Apoptosis;    HeLa cells;    Sequence analysis;    Colorimetric assays;    Drug design;    Phosphatases;    Protein domains;   

DOI  :  10.1371/journal.pone.0009981

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Background Previous studies established that PP1 is a target for Bcl-2 proteins and an important regulator of apoptosis. The two distinct functional PP1 consensus docking motifs, R/Kx(0,1)V/IxF and FxxR/KxR/K, involved in PP1 binding and cell death were previously characterized in the BH1 and BH3 domains of some Bcl-2 proteins.Principal Findings In this study, we demonstrate that DPT-AIF1, a peptide containing the AIF562–571 sequence located in a c-terminal domain of AIF, is a new PP1 interacting and cell penetrating molecule. We also showed that DPT-AIF1 provoked apoptosis in several human cell lines. Furthermore, DPT-APAF1 a bi-partite cell penetrating peptide containing APAF-1122–131, a non penetrating sequence from APAF-1 protein, linked to our previously described DPT-sh1 peptide shuttle, is also a PP1-interacting death molecule. Both AIF562–571 and APAF-1122–131 sequences contain a common R/Kx(0,1)V/IxFxxR/KxR/K motif, shared by several proteins involved in control of cell survival pathways. This motif combines the two distinct PP1c consensus docking motifs initially identified in some Bcl-2 proteins. Interestingly DPT-AIF2 and DPT-APAF2 that carry a F to A mutation within this combinatorial motif, no longer exhibited any PP1c binding or apoptotic effects. Moreover the F to A mutation in DPT-AIF2 also suppressed cell penetration.Conclusion These results indicate that the combinatorial PP1c docking motif R/Kx(0,1)V/IxFxxR/KxR/K, deduced from AIF562–571 and APAF-1122–131 sequences, is a new PP1c-dependent Apoptotic Signature. This motif is also a new tool for drug design that could be used to characterize potential anti-tumour molecules.

【 授权许可】

CC BY