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The Open Protein Structure Annotation Network
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2iay

    Table of contents
    1. 1. Protein Summary
    2. 2. Ligand Summary
    3. 3. References

    Title Structure of LP2179, the first representative of Pfam family PF08866, suggests a new fold with a role in amino-acid metabolism. Acta Crystallogr.,Sect.F 66 1205-1210 2010
    Site JCSG
    PDB Id 2iay Target Id
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    Molecular Characteristics
    Source
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    Alias Ids
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    TPS1533,NP_785678.1, BIG_467, BIG_55, 382659
    Molecular Weight
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    Da.
    Residues
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    Isoelectric Point
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    Sequence
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      BLAST   FFAS

    Structure Determination
    Method XRAY
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    Chains 1
    Resolution (Å)
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    Rfree
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    Matthews' coefficent 1.96 Rfactor 0.12
    Waters
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    Solvent Content 37.17

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    Ligand Information
    Ligands
    Metals

    Jmol

     
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    Google Scholar output for 2iay
    1. Structural classification of proteins and structural genomics: new insights into protein folding and evolution
    A Andreeva, AG Murzin - Acta Crystallographica Section F: Structural , 2010 - scripts.iucr.org
     
    2. Structure of LP2179, the first representative of Pfam family PF08866, suggests a new fold with a role in amino-acid metabolism
    C Bakolitsa, A Kumar, D Carlton, MD Miller - Section F: Structural , 2009 - scripts.iucr.org
     

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    Protein Summary

    The LP2179 gene of Lactobacillus plantarum, a lactic acid-producing bacterium found in human saliva and intestinal flora, is a member of the protein family PF08866 (DUF1831), an uncharacterized family of conserved bacterial proteins (COG3749). The LP2179 structure provides the first structural representative of this family, reveals a new fold and suggests a role in protein synthesis. 


    LP2179 forms a single domain composed of two anti-parallel β-sheets packed against a long C-terminal helix (Fig. 1). A second helix, H1, links strand β2 from the first β-sheet, formed by two N-terminal and the C-terminal β-strands (order: 127), to the second β-sheet (order: 3456) and packs parallel to H3. Pre-SCOP classifies LP2179 as an α+β protein that adopts a novel fold termed LP2179-like.

    2iay_rainbow.png

     

    Figure 1. Structure of LP2179. Stereo ribbon diagram, colored from blue to red going from N- to C-terminus, with secondary structure elements indicated.

     

    A search with FATCAT shows a significant structural similarity of LP2179 with members of the YugN-like family of proteins (PF08868) characterized by a TBP-like fold. Superposition of LP2179 onto ABC2387, a YugN-like homologue from Bacillus clausii (PDB id: 2pww) has an rmsd of 2.5 Å over 81 residues (Fig. 2A) and clearly reveals that these proteins share the same fold and topology over all helices and the second β-sheet (strands β3-β6), although the identity over the aligned residues is only 7%. Similar values are obtained for GK1089, another YugN-homolog from Geobacillus kaustophilus (PDB id: 2r5x, rmsd 2.9 Å over 87 residues with 10% sequence identity). Both YugN-like homologs show a break in the hydrogen-bonding pattern of strand β6, resulting in two shorter, collinear strands that hydrogen-bond seperately to β5. However, as the TBP-like fold is characterized by a β-α-β(4)-α topology, the only structural difference between the two families involves the first β-sheet in LP2179, which in YugN-like homologs is replaced by a β-strand that forms part of the single β-sheet (Fig. 2A).

     

    A search with FFAS shows no significant sequence similarity of LP2179 to any proteins of known structure. However, significant sequence similarity (20% identity) was observed between ABC2387 and RBSTP2229, a member of the protein family PF08968 (DUF1885) from Bacillus stearothermophilus. Like the YugN-like homologs, RBSTP2229 also exhibits a TBP-like fold. A structural superposition of ABC2387 (PDB id: 2pww) with RBSTP2229 (PDB id: 1t6a) shows a backbone RMSD of 2.8 Å over 57 residues. Over the same residue range, LP2179 shows a backbone RMSD of 3.3 Å  (Fig. 2B). In RBSTP2229, the length and orientation of helix H1 (pointing outwards from the structure instead of packing against the central β-sheet) differs from that observed in ABC2387 and LP2179, while the immediately succeeding β-strand is positioned at variable heights with respect to helix H3 in all three structures (Fig. 2A, 2B). Among these TBP-like variants, LP2179 is unique in combining the N- and C-terminal β-strands to form an additional β-sheet, situated between the central β-sheet and helix H3. However, both YugN-like and DUF1885 homologs display shorter variants of this secondary structure element in the same region (YugN-like homologs contain a single β-strand, DUF1185 forms a C-terminal hairpin), raising the possibility that this region might represent a locus for structural, and possibly functional, drift (Krishna 2005).

     

     

    Fig2_ABC_take2.png

     

     

    Figure 2. LP2179 exhibits structural similarity to members of the YugN-like family, DUF1885 and S-adenosylmethionine decarboxylases. Stereo-ribbon diagram showing the superposition of LP2179 (PDB id: 2iay, in blue) with, in gray: (A) a YugN-like homolog from Bacillus clausii (PDB id: 2pww), (B) a DUF1885 homolog from Geobacillus kaustophilus (PDB id: 1t6a), (C) S-adenosylmethionine decarboxylase proenzyme (TM0655) from Thermotoga maritima (PDB id: 1vr7).

     

    Finally, structural similarities of LP2179 to prokaryotic S-adenosylmethionine decarboxylases (AdoMetDC) (EC 4.1.1.50) were also observed. Superposition of LP2179 onto the AdoMetDC from Thermotoga maritima (PDB id: 1vr7) shows a backbone RMSD of 3.3 Å over 82 residues with 3% sequence identity (Fig. 2C). Similar values (RMSD of 3.3 Å over 67 residues with 3% sequence identity) were obtained for the AdoMetDC from Aquifex aeolicus (PDB id: 2iii). As with the YugN-like homologs, prokaryotic AdoMetDCs share a similar fold and topology as LP2179 along the second β-sheet and helices but additionally encompass the final strand of LP2179. The main differences involve the arrangement of the N- and C-terminal β-strands in prokaryotic AdoMetDCs that hydrogen-bond to form a single 6-stranded anti-parallel β-sheet, as opposed to the two separate sheets in LP2179, and a C-terminal helix absent in LP2179 (Fig. 2C).


    Structural comparison between these four Pfam families, reveals conservation of a core β-α-β(4)-α (TBP-like) fold with β-strand insertions added at the N- or C-terminus. YugN-like homologs contain an additional β-strand at the N-terminus (topology β(2)-α-β(4)-α) while PF08968 homologs show a circular permutation of the core fold with the N-terminal β-strand moved to the C-terminus (topology α-β(4)-α−β(2)). AdoMetDCs contain an additional β-strand at the C-terminus that hydrogen bonds with the N-terminal strand to form an antiparallel five-stranded β-sheet (topology β-α-β(4)-α−β). 

     

    [Cartoon topology diagram showing similarities and differences between these folds]

    [Discuss Russian doll effect]

     

    Protein structure is widely accepted as being better conserved than protein sequence, suggesting that structural relationships between proteins might provide information not available from sequence alone (see Kolodny 2006 for review). PF08866 (DUF1831), PF08868 (YugN-like) and PF08968 (DUF1885) are currently functionally uncharacterized protein families, specific to the Bacillus genus. AdoMetDC is a pyruvoyl-dependent amino acid decarboxylase involved in methionine metabolism and essential for polyamine biosynthesis (Pegg 1998). The structure of prokaryotic AdoMetDC proenzyme 20 reveals that despite the lack of detectable sequence similarity between the eukaryotic and prokaryotic forms of the enzyme (13% sequence identity), the two structures can be superimposed with an RMSD of 2.0 Å for 156 backbone residues and the catalytic site residues are conserved, thus providing an evolutionary link between the two forms of the enzyme (Toms 2004).

     

    The AdoMetDC catalytic site residues are not conserved in LP2179, the YugN-like and Pfam08968 homologs. However, a structure-based alignment reveals aromatic residue motifs conserved between the three families (Fig. 3). In LP2179 and YugN-like homologs, these motifs occur along the first two strands and intervening loop of the central β-sheet (β3, β4 in Fig. 1A) whereas in RBSTP2229, they are located at the end of the long N-terminal helix.

     

    Q88V95_LACPL      MAYTTTVKLDGDTKTYTLSPTVKKYTLMDL--GFVK-GRSGAFSFERSLDPTSP--YQAA 55
    Q5WFD8_BACSK    VKFPDTG-LEE--KEVAFS--IVNHAAKSL--GFI---HVDQWDYERVMFDYKIVHHEGT 50
    Q5L106_GEOKA    MKFENTG-LEN--QTVELS--RLDDIMERL--GFV---RAAQWDYERVTYDRKYVVKEGT 50
    P84137_BACST    MNTDLK-LPAG--KTMTIE--DVKQLLERYQMALKKTGEQLGWAYEQAAFPYTVRIHESV 55
                    :    .       :   :.    .        .:    .   : :*:     .    :..

    Q88V95_LACPL  FKLKM-------T-VNADLTGFK-MTTVTG-NGVQRANIF-KNDAHPEA-VEQLRYILAN 103
    Q5WFD8_BACSK FYLRVPAYAVKGEI-PRPSTIVQIMTPILGKYYYPHGVEY-EGETFPQAVIDKCNNKLAL 108
    Q5L106_GEOKA  YYLRVQGYAIEGNV-DSRYALIKLLTPILGKHYYPHGVEYGDDEHFPSSLVSQCQNVLAQ 109
    P84137_BACST    LYLQGDGRLYKGMAISVRTAGEETFIDIALPPGATHGDKG-KANEFSKWLAKTLGGELHL 114
                      *:               :  : :  :       :.    . : ...   .     * 

    Q88V95_LACPL  FIERD-ILTTD 113
    Q5WFD8_BACSK LA-KT-IKAEW 117
    Q5L106_GEOKA  VKSEL-EKIKE 119
    P84137_BACST  FSGRTMVFGSA 125
                    .  .      
     

     

    Figure 3.Structure-guided alignment of LP2179 and members of the YugN-like and DUF1885 families. UniProt abbreviations as follows: Q88V95_LACPL, gene locus lp_2179 from Lactobacillus plantarum; Q5WFD8_BACSK, gene locus ABC2387 from Bacillus clausii; Q5L106_GEOKA, gene locus GK1089 from Geobacillus kaustophilus; P84137_BACST, gene locus RBSTP2229 from Bacillus stearothermophilus

     

    The genome context (http://string.embl.de) of PF08868 and PF08968 have not been characterized. However, the genome context for LP2179 shows a high degree of confidence in a predicted functional association with a cysteine desulfurase (LP2180), a methylthioadenosine nucleosidase (LP2181), and a D-alanyl transfer protein (LP2016). Cysteine desulfurase (EC 2.8.1.7) catalyzes the production of alanine from cysteine while methylthioadenosine nucleosidase (EC 3.2.2.16) participates in amino group and methionine metabolism. Both enzymes are found in the genetic context of every member of the DUF1831 family, suggesting a role for DUF1831 in amino acid metabolism.

     

    In Gram-positive bacteria, such as the Bacillus genus, amino acid metabolism is directly coupled to several other metabolic pathways, including transsulfuration, polyamine synthesis and recycling, the activated methyl cycle and quorum sensing (Lebeer 2007). As previously mentioned, AdoMetDC is a central regulator of these pathways. Modified amino acids, such as homocysteine, or their catabolic products, such as polyamines, can serve both pathogenic and probiotic roles. In pathogenic bacteria, polyamines and homocysteine are involved in biofilm formation (Abraham 2006, Shah 2008), with polyamines also implicated in bacteriocin production and protection from acid and oxidative stress (Shah 2008). The probiotic role of lactobacilli is well documented (Ryan 2008), their antimicrobial activity resulting from the production of bacteriocins and antifungal peptides (De Vuyst 2007). The LP2179 structure and genome context suggest an involvement of DUF1831 in these coupled metabolic pathways. Further work will be required to determine whether the fold similarities observed between the Bacillus protein families described in this paper translate to similarities in function and whether this might involve a probiotic role.

    Ligand Summary



    References

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