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Novel conserved domains in proteins with predicted roles in eukaryotic cell-cycle regulation, decapping and RNA stability.

Anantharaman V, Aravind L - BMC Genomics (2004)

Bottom Line: The FDF domain is also found in the fungal Dcp3p-like and the animal FLJ22128-like proteins, where it fused to a C-terminal domain of the YjeF-N domain family.The Dcp3p and FLJ22128 proteins may localize to the cytoplasmic processing bodies and possibly catalyze a specific processing step in the decapping pathway.The explosive diversification of Sm domains appears to have played a role in the emergence of several uniquely eukaryotic ribonucleoprotein complexes, including those involved in decapping and mRNA stability.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA. ananthar@mail.nih.gov

ABSTRACT

Background: The emergence of eukaryotes was characterized by the expansion and diversification of several ancient RNA-binding domains and the apparent de novo innovation of new RNA-binding domains. The identification of these RNA-binding domains may throw light on the emergence of eukaryote-specific systems of RNA metabolism.

Results: Using sensitive sequence profile searches, homology-based fold recognition and sequence-structure superpositions, we identified novel, divergent versions of the Sm domain in the Scd6p family of proteins. This family of Sm-related domains shares certain features of conventional Sm domains, which are required for binding RNA, in addition to possessing some unique conserved features. We also show that these proteins contain a second previously uncharacterized C-terminal domain, termed the FDF domain (after a conserved sequence motif in this domain). The FDF domain is also found in the fungal Dcp3p-like and the animal FLJ22128-like proteins, where it fused to a C-terminal domain of the YjeF-N domain family. In addition to the FDF domains, the FLJ22128-like proteins contain yet another divergent version of the Sm domain at their extreme N-terminus. We show that the YjeF-N domains represent a novel version of the Rossmann fold that has acquired a set of catalytic residues and structural features that distinguish them from the conventional dehydrogenases.

Conclusions: Several lines of contextual information suggest that the Scd6p family and the Dcp3p-like proteins are conserved components of the eukaryotic RNA metabolism system. We propose that the novel domains reported here, namely the divergent versions of the Sm domain and the FDF domain may mediate specific RNA-protein and protein-protein interactions in cytoplasmic ribonucleoprotein complexes. More specifically, the protein complexes containing Sm-like domains of the Scd6p family are predicted to regulate the stability of mRNA encoding proteins involved in cell cycle progression and vesicular assembly. The Dcp3p and FLJ22128 proteins may localize to the cytoplasmic processing bodies and possibly catalyze a specific processing step in the decapping pathway. The explosive diversification of Sm domains appears to have played a role in the emergence of several uniquely eukaryotic ribonucleoprotein complexes, including those involved in decapping and mRNA stability.

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A Cartoon representation of the YjeF-N type Rossmann fold and its conserved features. The cartoon representation of the YjeF-N-type Rossmann fold domain was constructed using the crystal structure of the yeast YjeF-N domain containing protein (PDB: 1JZT). The N terminal helices are named N1 and N2, and the core helices and strands are named H1 to H7 and S1 to S8 respectively. The conserved residues of this fold corresponding to D16, E33, N69, N70, R79, H80, D138, D173 and T176 in this fold are shown in ball and stick representation. The salt bridges (E33 and R79 and H80) and hydrogen bonds (D138 and T176) between these conserved residues that are critical for the stabilization of the fold are shown as magenta dotted lines. The region between the strand 1 and helix 1 of the α/β core that corresponds to the glycine-rich nucleotide binding loop in the classic Rossmann fold (residues 66 and 72) is shown in red. Note the curvature of the central sheet and the packing of helix 1 of the α/β core and the second N-terminal additional helix.
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Figure 4: A Cartoon representation of the YjeF-N type Rossmann fold and its conserved features. The cartoon representation of the YjeF-N-type Rossmann fold domain was constructed using the crystal structure of the yeast YjeF-N domain containing protein (PDB: 1JZT). The N terminal helices are named N1 and N2, and the core helices and strands are named H1 to H7 and S1 to S8 respectively. The conserved residues of this fold corresponding to D16, E33, N69, N70, R79, H80, D138, D173 and T176 in this fold are shown in ball and stick representation. The salt bridges (E33 and R79 and H80) and hydrogen bonds (D138 and T176) between these conserved residues that are critical for the stabilization of the fold are shown as magenta dotted lines. The region between the strand 1 and helix 1 of the α/β core that corresponds to the glycine-rich nucleotide binding loop in the classic Rossmann fold (residues 66 and 72) is shown in red. Note the curvature of the central sheet and the packing of helix 1 of the α/β core and the second N-terminal additional helix.

Mentions: Further clues regarding the functions of the Dcp3p and FLJ21128 are furnished by an analysis of the C-terminal YjeF-N-type Rossmann fold domain. Both iterative sequence searches with the PSI-BLAST program and structural similarity searches of PDB show that the dehydrogenase-type Rossmann domains are their closest relatives. For example a PSI-BLAST search with the YjeF-N domain of Dcp3p recovers dehydrogenases with significant e-values (e = 10-5; iteration 6), while Ynl200cp (PDB:1jzt), a member of this family, recovers oxidoreductases like D-glycerate dehydrogenase with significant Z-scores (Z = 8.9) in structural similarity searches with the DALI program. However, a comparison of the sequence conservation pattern of the YjeF-N domains with that of the conventional Rossmann-fold dehydrogenases reveals several notable differences (Fig. 4 and Additional file 1). These include: 1) All members of this family contain two additional consecutive N-terminal helices that precede the first strand of the α/β core of the Rossmann fold and the core itself contains eight α/β units. Both these helices contain nearly absolutely conserved acidic residues. 2) The α/β core contains two characteristic aspartates; an absolutely conserved D at the end of strand 5 and one nearly universal D at end of strand 4. 3) The first helix of the α/β core of the Rossmann fold is extended by a whole turn resulting in the abbreviation of the glycine-rich nucleotide binding loop of the fold (Fig. 4). 4) The central sheet of the Rossmann fold is highly curved to form a peculiar barrel-like structure and the second additional N-terminal helix and the first helix of the α/β core pack against each other (Fig. 4). This structural quirk is chiefly stabilized by two sets of highly conserved interactions. Firstly, the salt-bridge and hydrogen-bonding interaction between the conserved acidic residue in the second N-terminal additional helix and the RH doublet in the first helix of the α/β core helps to positioning these two helices against one side of the curved sheet. Secondly, the hydrogen bonding between the conserved asparate at the end of strand 4 and the nearly absolutely conserved threonine C-terminal to strand 5 help in stabilizing the curvature of the central sheet (Fig. 4). 5) The acidic residue in the N-terminal-most additional helix of the YjeF-N, the acidic residue at the end of strand 5 and the polar residue (usually asparagine) from loop between strand 1 and helix 1 of the α/β core, line the mouth of the barrel- like structure to constitute the potential active site of this domain (Fig. 4).


Novel conserved domains in proteins with predicted roles in eukaryotic cell-cycle regulation, decapping and RNA stability.

Anantharaman V, Aravind L - BMC Genomics (2004)

A Cartoon representation of the YjeF-N type Rossmann fold and its conserved features. The cartoon representation of the YjeF-N-type Rossmann fold domain was constructed using the crystal structure of the yeast YjeF-N domain containing protein (PDB: 1JZT). The N terminal helices are named N1 and N2, and the core helices and strands are named H1 to H7 and S1 to S8 respectively. The conserved residues of this fold corresponding to D16, E33, N69, N70, R79, H80, D138, D173 and T176 in this fold are shown in ball and stick representation. The salt bridges (E33 and R79 and H80) and hydrogen bonds (D138 and T176) between these conserved residues that are critical for the stabilization of the fold are shown as magenta dotted lines. The region between the strand 1 and helix 1 of the α/β core that corresponds to the glycine-rich nucleotide binding loop in the classic Rossmann fold (residues 66 and 72) is shown in red. Note the curvature of the central sheet and the packing of helix 1 of the α/β core and the second N-terminal additional helix.
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Figure 4: A Cartoon representation of the YjeF-N type Rossmann fold and its conserved features. The cartoon representation of the YjeF-N-type Rossmann fold domain was constructed using the crystal structure of the yeast YjeF-N domain containing protein (PDB: 1JZT). The N terminal helices are named N1 and N2, and the core helices and strands are named H1 to H7 and S1 to S8 respectively. The conserved residues of this fold corresponding to D16, E33, N69, N70, R79, H80, D138, D173 and T176 in this fold are shown in ball and stick representation. The salt bridges (E33 and R79 and H80) and hydrogen bonds (D138 and T176) between these conserved residues that are critical for the stabilization of the fold are shown as magenta dotted lines. The region between the strand 1 and helix 1 of the α/β core that corresponds to the glycine-rich nucleotide binding loop in the classic Rossmann fold (residues 66 and 72) is shown in red. Note the curvature of the central sheet and the packing of helix 1 of the α/β core and the second N-terminal additional helix.
Mentions: Further clues regarding the functions of the Dcp3p and FLJ21128 are furnished by an analysis of the C-terminal YjeF-N-type Rossmann fold domain. Both iterative sequence searches with the PSI-BLAST program and structural similarity searches of PDB show that the dehydrogenase-type Rossmann domains are their closest relatives. For example a PSI-BLAST search with the YjeF-N domain of Dcp3p recovers dehydrogenases with significant e-values (e = 10-5; iteration 6), while Ynl200cp (PDB:1jzt), a member of this family, recovers oxidoreductases like D-glycerate dehydrogenase with significant Z-scores (Z = 8.9) in structural similarity searches with the DALI program. However, a comparison of the sequence conservation pattern of the YjeF-N domains with that of the conventional Rossmann-fold dehydrogenases reveals several notable differences (Fig. 4 and Additional file 1). These include: 1) All members of this family contain two additional consecutive N-terminal helices that precede the first strand of the α/β core of the Rossmann fold and the core itself contains eight α/β units. Both these helices contain nearly absolutely conserved acidic residues. 2) The α/β core contains two characteristic aspartates; an absolutely conserved D at the end of strand 5 and one nearly universal D at end of strand 4. 3) The first helix of the α/β core of the Rossmann fold is extended by a whole turn resulting in the abbreviation of the glycine-rich nucleotide binding loop of the fold (Fig. 4). 4) The central sheet of the Rossmann fold is highly curved to form a peculiar barrel-like structure and the second additional N-terminal helix and the first helix of the α/β core pack against each other (Fig. 4). This structural quirk is chiefly stabilized by two sets of highly conserved interactions. Firstly, the salt-bridge and hydrogen-bonding interaction between the conserved acidic residue in the second N-terminal additional helix and the RH doublet in the first helix of the α/β core helps to positioning these two helices against one side of the curved sheet. Secondly, the hydrogen bonding between the conserved asparate at the end of strand 4 and the nearly absolutely conserved threonine C-terminal to strand 5 help in stabilizing the curvature of the central sheet (Fig. 4). 5) The acidic residue in the N-terminal-most additional helix of the YjeF-N, the acidic residue at the end of strand 5 and the polar residue (usually asparagine) from loop between strand 1 and helix 1 of the α/β core, line the mouth of the barrel- like structure to constitute the potential active site of this domain (Fig. 4).

Bottom Line: The FDF domain is also found in the fungal Dcp3p-like and the animal FLJ22128-like proteins, where it fused to a C-terminal domain of the YjeF-N domain family.The Dcp3p and FLJ22128 proteins may localize to the cytoplasmic processing bodies and possibly catalyze a specific processing step in the decapping pathway.The explosive diversification of Sm domains appears to have played a role in the emergence of several uniquely eukaryotic ribonucleoprotein complexes, including those involved in decapping and mRNA stability.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA. ananthar@mail.nih.gov

ABSTRACT

Background: The emergence of eukaryotes was characterized by the expansion and diversification of several ancient RNA-binding domains and the apparent de novo innovation of new RNA-binding domains. The identification of these RNA-binding domains may throw light on the emergence of eukaryote-specific systems of RNA metabolism.

Results: Using sensitive sequence profile searches, homology-based fold recognition and sequence-structure superpositions, we identified novel, divergent versions of the Sm domain in the Scd6p family of proteins. This family of Sm-related domains shares certain features of conventional Sm domains, which are required for binding RNA, in addition to possessing some unique conserved features. We also show that these proteins contain a second previously uncharacterized C-terminal domain, termed the FDF domain (after a conserved sequence motif in this domain). The FDF domain is also found in the fungal Dcp3p-like and the animal FLJ22128-like proteins, where it fused to a C-terminal domain of the YjeF-N domain family. In addition to the FDF domains, the FLJ22128-like proteins contain yet another divergent version of the Sm domain at their extreme N-terminus. We show that the YjeF-N domains represent a novel version of the Rossmann fold that has acquired a set of catalytic residues and structural features that distinguish them from the conventional dehydrogenases.

Conclusions: Several lines of contextual information suggest that the Scd6p family and the Dcp3p-like proteins are conserved components of the eukaryotic RNA metabolism system. We propose that the novel domains reported here, namely the divergent versions of the Sm domain and the FDF domain may mediate specific RNA-protein and protein-protein interactions in cytoplasmic ribonucleoprotein complexes. More specifically, the protein complexes containing Sm-like domains of the Scd6p family are predicted to regulate the stability of mRNA encoding proteins involved in cell cycle progression and vesicular assembly. The Dcp3p and FLJ22128 proteins may localize to the cytoplasmic processing bodies and possibly catalyze a specific processing step in the decapping pathway. The explosive diversification of Sm domains appears to have played a role in the emergence of several uniquely eukaryotic ribonucleoprotein complexes, including those involved in decapping and mRNA stability.

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Related in: MedlinePlus