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CRYSTAL STRUCTURE OF YAGE, A PROPHAGE PROTEIN BELONGING TO THE DIHYDRODIPICOLINIC ACID SYNTHASE FAMILY FROM E. COLI K12

INTRODUCTION. The incorporation of genetic material from other organisms into bacterial genomes potentiates novel forms of drug resistance or pathogenicity. One method of incorporation is through infection by a bacteriophage, which enters the lysogenic life cycle. Excision of the phage genome as a result of induction may include some of the host's genome, and subsequent infection and lysogeny in other bacteria would incorporate this nonphage DNA into these hosts. Loss of ability to excise itself from the host leads to the permanent addition in the host genome of the phage genes and other genetic material that may have accumulated during previous lysogenic phases. In this project, targets were chosen initially from proteins encoded by prophages present in E. coli K12 based on possible similarities to known virulence factors from pathogenic bacteria, whose three-dimensional structures are unknown. One such target was the yagE gene located in the E. coli K12 genome that is part of prophage CP4-6 encoding a 33-kDa putative dihydrodipicolinate synthase (DHDPS)-like protein (UniProtKB/Swiss-prot: P75682). The DHDPS-like domain belongs to the N-acetyl neuraminate lyase (NAL) subfamily containing an eight-fold (TIM barrel) with a small C-terminal α-helical domain (Inter pro: IPR005263). The DHDPS domain is present in a wide variety of enzymes. For example, NAL, which is involved in sialic acid metabolism, trans-o-hydroxybenzylidine pyruvate hydratase aldolase (HBPHA) in naphthalene degradation, D-4-deoxy-5-oxoglucarate dehydratase (DOGDH) in glucarate metabolism, 2-keta-3-deoxy gluconate aldolase (KDGA) in the Entner-Duodoroff pathway, and dihydrodipicolinate synthase (DHDPS) in lysine biosynthesis. All these enzymes contain an eight-fold α/β barrel and a small C-terminal α-helical region. The TIM barrel and the C-terminal α-helical region together constitute the DHDPS-like protein structure.

RESULTS AND DISCUSSION. Cartoon representation of YagE showing the twofold symmetry axes between monomers. Chain A is colored cyan, Chain B, green, Chain C, magenta, and Chain D, yellow. of YagE (cyan) with (1nal, yellow), (1w3i, magenta), (1xky, green), and (2ats, blue) monomers. Even though YagE has only 23, 24, and 27% sequence identity with EcNAL, SsKDGA, EcDHDPS, respectively, their monomeric structures are all very similar, with the β-strands being highly superposable. Superposition of active site region residues of YagE with (1w3i), (2ats), and (1nal), with amino acids labels are from the respective PDB structures. Members of the NAL subfamily of proteins are known to have very similar active sites and a single amino acid change can drastically alter the function. This is seen, for example, in the case of NAL (1nal), which can gain DHDPS activity by altering a (orange) to (blue) at position 142. The possible active site region of YagE shows closest sequence resemblance to the active site of KDG aldolase from SsKDGA (1w3i) and NAL from EcNAL (1nal), suggesting that, possibly, this protein can perform either of these functions. Although the active site of EcDHDPS (1xky) and BaDHDPS (2ats) shows similarities, the important residue that differentiates between NAL and DHDPS, namely Leu142 (in 1nal), is also present in YagE at that particular position suggesting that the protein might perform more of a NAL-related than DHDPS-related function. In summary, the high-resolution structure of YagE provides a first view of this protein, which is identified here as a putative member of the well-characterized NAL subfamily of proteins. This analysis has suggested two possible functions based on sequence and structure alignment with known NAL subfamily members. Even though the exact molecular function for the protein is not immediately evident, the structure provides a framework to deduce and assay molecular function based on clustered conserved residues and the putative active site.

About this Structure

2V9D is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.

Reference

Crystal structure of YagE, a putative DHDPS-like protein from Escherichia coli K12., Manicka S, Peleg Y, Unger T, Albeck S, Dym O, Greenblatt HM, Bourenkov G, Lamzin V, Krishnaswamy S, Sussman JL, Proteins. 2008 Jun;71(4):2102-8. PMID:18361457

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