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Analysis of proteins with the 'hot dog' fold: prediction of function and identification of catalytic residues of hypothetical proteins.

Pidugu LS, Maity K, Ramaswamy K, Surolia N, Suguna K - BMC Struct. Biol. (2009)

Bottom Line: The hot dog fold has been found in more than sixty proteins since the first report of its existence about a decade ago.This study reveals that though the basic architecture of the fold is well conserved in these proteins, significant differences exist in their sequence, nature of substrate and oligomerization.The analysis led to predictions regarding the functional classification and identification of possible catalytic residues of a number of hot dog fold-containing hypothetical proteins whose structures were determined in high throughput structural genomics projects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India. plsmukhi@gmail.com

ABSTRACT

Background: The hot dog fold has been found in more than sixty proteins since the first report of its existence about a decade ago. The fold appears to have a strong association with fatty acid biosynthesis, its regulation and metabolism, as the proteins with this fold are predominantly coenzyme A-binding enzymes with a variety of substrates located at their active sites.

Results: We have analyzed the structural features and sequences of proteins having the hot dog fold. This study reveals that though the basic architecture of the fold is well conserved in these proteins, significant differences exist in their sequence, nature of substrate and oligomerization. Segments with certain conserved sequence motifs seem to play crucial structural and functional roles in various classes of these proteins.

Conclusion: The analysis led to predictions regarding the functional classification and identification of possible catalytic residues of a number of hot dog fold-containing hypothetical proteins whose structures were determined in high throughput structural genomics projects.

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Different modes of CoA binding. The dimer of a 4HBT-II protein (PDB code: 1Q4T) is shown in cartoon representation and the bound CoA molecules in green. The CoA molecules of a 4HBT-I protein (1LO7) with a different binding mode are in yellow. Catalytic residues are shown in ball and stick representation.
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Figure 10: Different modes of CoA binding. The dimer of a 4HBT-II protein (PDB code: 1Q4T) is shown in cartoon representation and the bound CoA molecules in green. The CoA molecules of a 4HBT-I protein (1LO7) with a different binding mode are in yellow. Catalytic residues are shown in ball and stick representation.

Mentions: Various substituents of acyl-CoA serve as substrates for most of the hot dog fold binding proteins. There are 12 crystal structures of various hot dog fold proteins complexed with different CoA molecules. The CoA molecule binds to the hot dog fold proteins in two different binding modes. In both cases, CoA binds near the active site in a curved conformation with the groups substituted at the 4'-phosphopantetheine arm located in the active site tunnel (Fig. 10). The β-mercaptoethylamine and pantothenate units are mostly solvent exposed and are stabilized by hydrogen bonds to the backbone of the C-terminal loop of the β-strand at the dimer interface. The major difference in the two modes of binding is the orientation of the nucleotide moiety. In the case of hot dog fold proteins with quaternary associations of the type D, TA, H2, DdhA, the 3'-phosphate interacts with the loop mentioned above and the nucleotide interacts with the convex surface of the curved β-sheet. In the case of hotdog fold proteins that have a quaternary association of the type TB and DdhB due to back to back stacking of the β-sheet, the 4'-phosphopantetheine arm winds in the opposite direction directing the nucleotide away from the β-sheet and is more solvent exposed. Within the TB mode of quaternary association, the 4HBT-II subfamily proteins show all site reactivity, while in PaaI from T. thermophilus half the site reactivity has been reported [23].


Analysis of proteins with the 'hot dog' fold: prediction of function and identification of catalytic residues of hypothetical proteins.

Pidugu LS, Maity K, Ramaswamy K, Surolia N, Suguna K - BMC Struct. Biol. (2009)

Different modes of CoA binding. The dimer of a 4HBT-II protein (PDB code: 1Q4T) is shown in cartoon representation and the bound CoA molecules in green. The CoA molecules of a 4HBT-I protein (1LO7) with a different binding mode are in yellow. Catalytic residues are shown in ball and stick representation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2698920&req=5

Figure 10: Different modes of CoA binding. The dimer of a 4HBT-II protein (PDB code: 1Q4T) is shown in cartoon representation and the bound CoA molecules in green. The CoA molecules of a 4HBT-I protein (1LO7) with a different binding mode are in yellow. Catalytic residues are shown in ball and stick representation.
Mentions: Various substituents of acyl-CoA serve as substrates for most of the hot dog fold binding proteins. There are 12 crystal structures of various hot dog fold proteins complexed with different CoA molecules. The CoA molecule binds to the hot dog fold proteins in two different binding modes. In both cases, CoA binds near the active site in a curved conformation with the groups substituted at the 4'-phosphopantetheine arm located in the active site tunnel (Fig. 10). The β-mercaptoethylamine and pantothenate units are mostly solvent exposed and are stabilized by hydrogen bonds to the backbone of the C-terminal loop of the β-strand at the dimer interface. The major difference in the two modes of binding is the orientation of the nucleotide moiety. In the case of hot dog fold proteins with quaternary associations of the type D, TA, H2, DdhA, the 3'-phosphate interacts with the loop mentioned above and the nucleotide interacts with the convex surface of the curved β-sheet. In the case of hotdog fold proteins that have a quaternary association of the type TB and DdhB due to back to back stacking of the β-sheet, the 4'-phosphopantetheine arm winds in the opposite direction directing the nucleotide away from the β-sheet and is more solvent exposed. Within the TB mode of quaternary association, the 4HBT-II subfamily proteins show all site reactivity, while in PaaI from T. thermophilus half the site reactivity has been reported [23].

Bottom Line: The hot dog fold has been found in more than sixty proteins since the first report of its existence about a decade ago.This study reveals that though the basic architecture of the fold is well conserved in these proteins, significant differences exist in their sequence, nature of substrate and oligomerization.The analysis led to predictions regarding the functional classification and identification of possible catalytic residues of a number of hot dog fold-containing hypothetical proteins whose structures were determined in high throughput structural genomics projects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India. plsmukhi@gmail.com

ABSTRACT

Background: The hot dog fold has been found in more than sixty proteins since the first report of its existence about a decade ago. The fold appears to have a strong association with fatty acid biosynthesis, its regulation and metabolism, as the proteins with this fold are predominantly coenzyme A-binding enzymes with a variety of substrates located at their active sites.

Results: We have analyzed the structural features and sequences of proteins having the hot dog fold. This study reveals that though the basic architecture of the fold is well conserved in these proteins, significant differences exist in their sequence, nature of substrate and oligomerization. Segments with certain conserved sequence motifs seem to play crucial structural and functional roles in various classes of these proteins.

Conclusion: The analysis led to predictions regarding the functional classification and identification of possible catalytic residues of a number of hot dog fold-containing hypothetical proteins whose structures were determined in high throughput structural genomics projects.

Show MeSH