The crystal structure of the C-terminal DAP5/p97 domain sheds light on the molecular basis for its processing by caspase cleavage.

Journal of Molecular Biology
Noa LibermanAdi Kimchi

Abstract

DAP5/p97 (death-associated protein 5) is a member of the eukaryotic translation initiation factor 4G family. It functions as a scaffold protein promoting cap-independent translation of proteins. During apoptosis, DAP5/p97 is cleaved by caspases at position 792, yielding an 86-kDa C-terminal truncated isoform (DAP5/p86) that promotes translation of several mRNAs mediated by an internal ribosome entry site. In this study, we report the crystal structure of the C-terminal region of DAP5/p97 extending between amino acids 730 and 897. This structure consists of four HEAT-Repeats and is homologous to the C-terminal domain of eIF4GI, eIF5, and eIF2Bepsilon. Unlike the other proteins, DAP5/p97 lacks electron density in the loop connecting alpha3 and alpha4, which harbors the caspase cleavage site. Moreover, we observe fewer interactions between these two helices. Thus, previous mapping of this site by mutation analysis is confirmed here by the resolved structure of the DAP5/p97 C-terminus. In addition, we identified the position of two conserved aromatic and acidic boxes in the structure of the DAP5/p97 C-terminus. The acidic residues in the two aromatic and acidic boxes form a continuous negatively charged patch, which is suggested to...Continue Reading

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Citations

Jul 13, 2011·Nucleic Acids Research·Chingakham Ranjit SinghKatsura Asano
Jan 9, 2010·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Filipp FrankBhushan Nagar
Nov 28, 2013·PloS One·David FournierMiguel A Andrade-Navarro
Jun 15, 2010·Proteins·Shilong FanWeimin Gong
Mar 18, 2015·Nucleic Acids Research·Noa LibermanNahum Sonenberg

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