The crystal structure of the eIF4A-PDCD4 complex has been determined, revealing that PDCD4 inhibits eIF4A through two different binding modes. PDCD4 binds to the surface grooves of both domains of eIF4A, blocking the hinge-bending movement between the NTD and CTD of eIF4A. The recognition of eIF4A by PDCD4 through the two-MA3-binding mode is important for the PDCD4-mediated inhibition of eIF4A and translation. The two different binding modes may allow PDCD4 to overcome mutational effects on a local region in a single MA3, which could otherwise abrogate the function of PDCD4.
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Programmed cell death protein 4 (PDCD4) is a translation inhibitor that suppresses neoplastic transformation in cultured cells and transgenic mice
Loss or reduced expression of PDCD4 has been implicated in the development and progression of a variety of aggressive human cancers
PDCD4 is regulated by the S6K1 kinase and the SCFβTRCP ubiquitin ligase in response to the activation of the mTOR pathway by mitogens, and the controlled degradation of PDCD4 is essential for efficient protein synthesis and consequently for cell growth and proliferation
eIF4A is a DEAD-box RNA helicase, with two domains, that unwinds the secondary structures in 5′-untranslated region (UTR) and cap of mRNA and thereby facilitates ribosome scanning (8). eIF4G is an adaptor protein that coordinates assembly of translation factors and the small ribosomal subunit (8). PDCD4 is believed to inhibit cap-dependent translat...
PDCD4 is formed with the two MA3 domains at its middle (mMA3) and C-terminal regions (cMA3)
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