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Solution structure of the RWD domain of the mouse GCN2 protein

¹ RIKEN Genomic Sciences Center, Tsurumi, Yokohama, Japan
² RIKEN Harima Institute at SPring-8, Sayo, Hyogo, Japan
³ Graduate School of Integrated Science, Yokohama City University, Yokohama, Japan
⁴ Structure and Function of Biomolecules, PRESTO, Japan Science and Technology Agency, Saitama, Japan
⁵ Department of Biophysics and Biochemistry, Graduate School of Science, the University of Tokyo, Tokyo, Japan

(RECEIVED March 18, 2004; FINAL REVISION May 18, 2004; ACCEPTED May 18, 2004)

GCN2 is the -subunit of the only translation initiation factor (eIF2) kinase that appears in all eukaryotes. Its function requires an interaction with GCN1 via the domain at its N-terminus, which is termed the RWD domain after three major RWD-containing proteins: RING finger-containing proteins, WD-repeat-containing proteins, and yeast DEAD (DEXD)-like helicases. In this study, we determined the solution structure of the mouse GCN2 RWD domain using NMR spectroscopy. The structure forms an + sandwich fold consisting of two layers: a four-stranded antiparallel -sheet, and three side-by-side -helices, with an topology. A characteristic YPXXXP motif, which always occurs in RWD domains, forms a stable loop including three consecutive -turns that overlap with each other by two residues (triple -turn). As putative binding sites with GCN1, a structure-based alignment allowed the identification of several surface residues in -helix 3 that are characteristic of the GCN2 RWD domains. Despite the apparent absence of sequence similarity, the RWD structure significantly resembles that of ubiquitin-conjugating enzymes (E2s), with most of the structural differences in the region connecting -strand 4 and -helix 3. The structural architecture, including the triple -turn, is fundamentally common among various RWD domains and E2s, but most of the surface residues on the structure vary. Thus, it appears that the RWD domain is a novel structural domain for protein-binding that plays specific roles in individual RWD-containing proteins.

Keywords: NMR; GI domain; hydrogen bond network; protection factor; protein structure

Reprint requests to: Shigeyuki Yokoyama, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan; e-mail: yokoyama{at}biochem.s.u-tokyo.ac.jp; fax: 81-45-503-9195.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04751804.

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