Structure of the C-terminal MA-3 domain of the tumour suppressor protein Pdcd4 and characterization of its interaction with eIF4A

Programmed cell death protein 4 (Pdcd4) is a novel tumour suppressor protein, which is involved in the control of eukaryotic transcription and translation. The regulation of translation involves specific interactions with eukaryotic initiation factor (eIF)4A and eIF4G, which are mediated via the two...

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Bibliographic Details
Published in:	Oncogene Vol. 26; no. 34; pp. 4941 - 4950
Main Authors:	WATERS, L. C, VEVERKA, V, BÖHM, M, SCHMEDT, T, CHOONG, P. T, MUSKETT, F. W, KLEMPNAUER, K.-H, CARR, M. D
Format:	Journal Article
Language:	English
Published:	Basingstoke Nature Publishing 26-07-2007 Nature Publishing Group
Subjects:	Amino Acid Sequence Animals Apoptosis Apoptosis Regulatory Proteins - chemistry Binding Sites Biological and medical sciences Cancer Cell death Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Conserved sequence Eukaryotic Initiation Factor-4A - chemistry Fundamental and applied biological sciences. Psychology Gene regulation Genetic aspects Genetics Homology Initiation factor eIF-4G Mice Models, Molecular Molecular and cellular biology Molecular Sequence Data Molecular structure NMR Nuclear magnetic resonance Nuclear Magnetic Resonance, Biomolecular Nucleotide sequence Physiological aspects Protein Structure, Tertiary Proteins RNA-Binding Proteins - chemistry Spectrum analysis Structural Homology, Protein Transcription Tumor suppressor genes Tumor Suppressor Proteins - chemistry Tumors United Kingdom Germany Characterization HEAT NMR translation MA-3 Pdcd4 Carcinogenesis Protein eIF4A Tumor suppressor gene
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Summary:	Programmed cell death protein 4 (Pdcd4) is a novel tumour suppressor protein, which is involved in the control of eukaryotic transcription and translation. The regulation of translation involves specific interactions with eukaryotic initiation factor (eIF)4A and eIF4G, which are mediated via the two tandem MA-3 domains. We have determined the structure of the C-terminal MA-3 domain of Pdcd4 (Pdcd4 MA-3(C)), characterized its interaction with eIF4A and compared the features of nuclear magnetic resonance (NMR) spectra obtained from the single domain and tandem MA-3 region. Pdcd4 MA-3(C) is composed of three layers of helix-turn-helix hairpins capped by a single helix and shows close structural homology to the atypical HEAT repeats found in many eIFs. The sequence conservation and NMR data strongly suggest that the tandem MA-3 region is composed of two equivalent domains connected by a somewhat flexible linker. Pdcd4 MA-3(C) was found to interact with the N-terminal domain of eIF4A through a conserved surface region encompassing the loop connecting alpha5 and alpha6 and the turn linking alpha3 and alpha4. This site is strongly conserved in other MA-3 domains known to interact with eIF4A, including the preceding domain of Pdcd4, suggesting a common mode of binding.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/sj.onc.1210305