Title

Random Mutagenesis Of PdzOmi Domain And Selection Of Mutants That Specifically Bind The Myc Proto-Oncogene And Induce Apoptosis

Keywords

Apoptosis; Myc proto-oncogene; Omi/HtrA2; PDZ domains; Protein design; Protein-protein interactions; Yeast two-hybrid system

Abstract

Omi is a mammalian serine protease that is localized in the mitochondria and released to the cytoplasm in response to apoptotic stimuli. Omi induces cell death in a caspase-dependent manner by interacting with the X-chromosome linked inhibitor of apoptosis protein, as well as in a caspase-independent way that relies on its proteolytic activity. Omi is synthesized as a precursor polypeptide and is processed to an active serine protease with a unique PDZ domain. PDZ domains recognize the extreme carboxyl terminus of target proteins. Internal peptides that are able to fold into a β-finger are also reported to bind some PDZ domains. Using a modified yeast two-hybrid system, PDZOmi mutants were isolated by their ability to bind the carboxyl terminus of human Myc oncoprotein in yeast as well as in mammalian cells. One such PDZm domain (PDZ-M1), when transfected into mammalian cells, was able to bind to endogenous Myc protein and induce cell death. PDZ-M1-induced apoptosis was entirely dependent on the presence of Myc protein and was not observed when c-myc null fibroblasts were used. Our studies indicate that the PDZ domain of Omi can provide a prototype that could easily be exploited to target specifically and inactivate oncogenes by binding to their unique carboxyl terminus.

Publication Date

5-8-2003

Publication Title

Oncogene

Volume

22

Issue

18

Number of Pages

2772-2781

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1038/sj.onc.1206359

Socpus ID

0038631772 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/0038631772

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