Analysis of Multiple HPV E6 PDZ Interactions Defines Type-Specific PDZ Fingerprints That Predict Oncogenic Potential

PLoS Pathogens

Corrado Guarnaccia¹  Michael P. Myers²  Miranda Thomas³  Lawrence Banks³  Paola Massimi³ 

[1] Biotechnology Development, International Centre for Genetic Engineering and Biotechnology (I.C.G.E.B.), Trieste, Italy;Protein Networks, International Centre for Genetic Engineering and Biotechnology (I.C.G.E.B.), Trieste, Italy;Tumour Virology, International Centre for Genetic Engineering and Biotechnology (I.C.G.E.B.), Trieste, Italy

关键词: Human papillomavirus;    HPV-18;    HPV-16;    Protein domains;    Carcinogenesis;    Glutathione chromatography;    Mass spectrometry;    Prisms;   

DOI  :  10.1371/journal.ppat.1005766

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The high-risk Human Papillomavirus (HPV) E6 oncoproteins are characterised by the presence of a class I PDZ-binding motif (PBM) on their extreme carboxy termini. The PBM is present on the E6 proteins derived from all cancer-causing HPV types, but can also be found on some related non-cancer-causing E6 proteins. We have therefore been interested in investigating the potential functional differences between these different E6 PBMs. Using an unbiased proteomic approach in keratinocytes, we have directly compared the interaction profiles of these different PBMs. This has allowed us to identify the potential PDZ target fingerprints of the E6 PBMs from 7 different cancer-causing HPV types, from 3 HPV types with weak cancer association, and from one benign HPV type that possesses an ancestral PBM. We demonstrate a striking increase in the number of potential PDZ targets bound by each E6 PBM as cancer-causing potential increases, and show that the HPV-16 and HPV-18 PBMs have the most flexibility in their PDZ target selection. Furthermore, the specific interaction with hScrib correlates directly with increased oncogenic potential. In contrast, hDlg is bound equally well by all the HPV E6 PBMs analysed, indicating that this is an evolutionarily conserved interaction, and was most likely one of the original E6 PBM target proteins that was important for the occupation of a potential new niche. Finally, we present evidence that the cell junction components ZO-2 and β-2 syntrophin are novel PDZ domain–containing targets of a subset of high-risk HPV types.

【 授权许可】

CC BY