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Molecular phylogeny of the kelch-repeat superfamily reveals an expansion of BTB/kelch proteins in animals.

Prag S, Adams JC - BMC Bioinformatics (2003)

Bottom Line: Expansion of the family during the evolution of multicellular animals is mainly accounted for by a major expansion of the BTB/kelch domain architecture.BTB/kelch proteins constitute 72 % of the kelch-repeat superfamily of H. sapiens and form three subgroups, one of which appears the most-conserved during evolution.Distinctions in propeller blade organisation between subgroups 1 and 2 were identified that could provide new direction for biochemical and functional studies of novel kelch-repeat proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA. sprag@tiscali.co.uk

ABSTRACT

Background: The kelch motif is an ancient and evolutionarily-widespread sequence motif of 44-56 amino acids in length. It occurs as five to seven repeats that form a beta-propeller tertiary structure. Over 28 kelch-repeat proteins have been sequenced and functionally characterised from diverse organisms spanning from viruses, plants and fungi to mammals and it is evident from expressed sequence tag, domain and genome databases that many additional hypothetical proteins contain kelch-repeats. In general, kelch-repeat beta-propellers are involved in protein-protein interactions, however the modest sequence identity between kelch motifs, the diversity of domain architectures, and the partial information on this protein family in any single species, all present difficulties to developing a coherent view of the kelch-repeat domain and the kelch-repeat protein superfamily. To understand the complexity of this superfamily of proteins, we have analysed by bioinformatics the complement of kelch-repeat proteins encoded in the human genome and have made comparisons to the kelch-repeat proteins encoded in other sequenced genomes.

Results: We identified 71 kelch-repeat proteins encoded in the human genome, whereas 5 or 8 members were identified in yeasts and around 18 in C. elegans, D. melanogaster and A. gambiae. Multiple domain architectures were identified in each organism, including previously unrecognised forms. The vast majority of kelch-repeat domains are predicted to form six-bladed beta-propellers. The most prevalent domain architecture in the metazoan animal genomes studied was the BTB/kelch domain organisation and we uncovered 3 subgroups of human BTB/kelch proteins. Sequence analysis of the kelch-repeat domains of the most robustly-related subgroups identified differences in beta-propeller organisation that could provide direction for experimental study of protein-binding characteristics.

Conclusion: The kelch-repeat superfamily constitutes a distinct and evolutionarily-widespread family of beta-propeller domain-containing proteins. Expansion of the family during the evolution of multicellular animals is mainly accounted for by a major expansion of the BTB/kelch domain architecture. BTB/kelch proteins constitute 72 % of the kelch-repeat superfamily of H. sapiens and form three subgroups, one of which appears the most-conserved during evolution. Distinctions in propeller blade organisation between subgroups 1 and 2 were identified that could provide new direction for biochemical and functional studies of novel kelch-repeat proteins.

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The kelch motif and the β-propeller fold. A, Consensus sequence of the kelch motif. Compiled from [2] and [3]. The sequence motif is shown in relation to the four β-sheets of a propeller blade structure, as determined for the kelch motifs of fungal galactose oxidase [4]. In the consensus, G= glycine, Y = tyrosine, W = tryptophan, s = small residue; l = large residue; h = hydrophobic residue. B, Structure of a kelch-repeat propeller blade. A single blade from the crystal structure of fungal galactose oxidase (1GOF) is shown. β sheets 1–4 are colored as in panel A. The N- and C-termini join to adjacent blades. As indicated by the mapping of the consensus amino acids onto the blade, the most highly-conserved residues are located in the β-sheets. In various examples of β-propeller proteins, the intra- and inter-blade loops have variable sequences and contribute to protein-protein interactions [3]. C, Structure of the kelch-repeat β-propeller domain of fungal galactose oxidase (1GOF). β-sheets 1–4 in each blade are colored as in panel A. As indicated, this β-propeller contains seven blades. The β-4 strand of blade 7 is derived from the amino-terminus of the domain and thus closes the circular structure.
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Figure 1: The kelch motif and the β-propeller fold. A, Consensus sequence of the kelch motif. Compiled from [2] and [3]. The sequence motif is shown in relation to the four β-sheets of a propeller blade structure, as determined for the kelch motifs of fungal galactose oxidase [4]. In the consensus, G= glycine, Y = tyrosine, W = tryptophan, s = small residue; l = large residue; h = hydrophobic residue. B, Structure of a kelch-repeat propeller blade. A single blade from the crystal structure of fungal galactose oxidase (1GOF) is shown. β sheets 1–4 are colored as in panel A. The N- and C-termini join to adjacent blades. As indicated by the mapping of the consensus amino acids onto the blade, the most highly-conserved residues are located in the β-sheets. In various examples of β-propeller proteins, the intra- and inter-blade loops have variable sequences and contribute to protein-protein interactions [3]. C, Structure of the kelch-repeat β-propeller domain of fungal galactose oxidase (1GOF). β-sheets 1–4 in each blade are colored as in panel A. As indicated, this β-propeller contains seven blades. The β-4 strand of blade 7 is derived from the amino-terminus of the domain and thus closes the circular structure.

Mentions: The kelch motif is an ancient and evolutionarily-widespread sequence motif of 44–56 amino acids in length. Eight residues within the motif are highly-conserved and constitute a consensus sequence [1-3] (Fig. 1A). Kelch motifs occur as groups of five to seven repeats and have been identified in proteins of otherwise distinct molecular architecture, termed the kelch-repeat superfamily. Currently, over 28 kelch-repeat proteins have been sequenced and functionally characterised in diverse organisms including viruses, plants, fungi and mammals [3]. Several kelch repeat-containing proteins have been recognised in Bacteria and Archaea (GenBank NP_713516, NP_639451 and Pfam01344 species distribution link), revealing the universal nature of the repeats. On the basis of the crystal structure determined for a single kelch-repeat protein, Hypomyces rosellus galactose oxidase (PDB 1GOF), the sets of repeated kelch motifs are predicated to form a β-propeller structure [2,4].


Molecular phylogeny of the kelch-repeat superfamily reveals an expansion of BTB/kelch proteins in animals.

Prag S, Adams JC - BMC Bioinformatics (2003)

The kelch motif and the β-propeller fold. A, Consensus sequence of the kelch motif. Compiled from [2] and [3]. The sequence motif is shown in relation to the four β-sheets of a propeller blade structure, as determined for the kelch motifs of fungal galactose oxidase [4]. In the consensus, G= glycine, Y = tyrosine, W = tryptophan, s = small residue; l = large residue; h = hydrophobic residue. B, Structure of a kelch-repeat propeller blade. A single blade from the crystal structure of fungal galactose oxidase (1GOF) is shown. β sheets 1–4 are colored as in panel A. The N- and C-termini join to adjacent blades. As indicated by the mapping of the consensus amino acids onto the blade, the most highly-conserved residues are located in the β-sheets. In various examples of β-propeller proteins, the intra- and inter-blade loops have variable sequences and contribute to protein-protein interactions [3]. C, Structure of the kelch-repeat β-propeller domain of fungal galactose oxidase (1GOF). β-sheets 1–4 in each blade are colored as in panel A. As indicated, this β-propeller contains seven blades. The β-4 strand of blade 7 is derived from the amino-terminus of the domain and thus closes the circular structure.
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Related In: Results  -  Collection

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Figure 1: The kelch motif and the β-propeller fold. A, Consensus sequence of the kelch motif. Compiled from [2] and [3]. The sequence motif is shown in relation to the four β-sheets of a propeller blade structure, as determined for the kelch motifs of fungal galactose oxidase [4]. In the consensus, G= glycine, Y = tyrosine, W = tryptophan, s = small residue; l = large residue; h = hydrophobic residue. B, Structure of a kelch-repeat propeller blade. A single blade from the crystal structure of fungal galactose oxidase (1GOF) is shown. β sheets 1–4 are colored as in panel A. The N- and C-termini join to adjacent blades. As indicated by the mapping of the consensus amino acids onto the blade, the most highly-conserved residues are located in the β-sheets. In various examples of β-propeller proteins, the intra- and inter-blade loops have variable sequences and contribute to protein-protein interactions [3]. C, Structure of the kelch-repeat β-propeller domain of fungal galactose oxidase (1GOF). β-sheets 1–4 in each blade are colored as in panel A. As indicated, this β-propeller contains seven blades. The β-4 strand of blade 7 is derived from the amino-terminus of the domain and thus closes the circular structure.
Mentions: The kelch motif is an ancient and evolutionarily-widespread sequence motif of 44–56 amino acids in length. Eight residues within the motif are highly-conserved and constitute a consensus sequence [1-3] (Fig. 1A). Kelch motifs occur as groups of five to seven repeats and have been identified in proteins of otherwise distinct molecular architecture, termed the kelch-repeat superfamily. Currently, over 28 kelch-repeat proteins have been sequenced and functionally characterised in diverse organisms including viruses, plants, fungi and mammals [3]. Several kelch repeat-containing proteins have been recognised in Bacteria and Archaea (GenBank NP_713516, NP_639451 and Pfam01344 species distribution link), revealing the universal nature of the repeats. On the basis of the crystal structure determined for a single kelch-repeat protein, Hypomyces rosellus galactose oxidase (PDB 1GOF), the sets of repeated kelch motifs are predicated to form a β-propeller structure [2,4].

Bottom Line: Expansion of the family during the evolution of multicellular animals is mainly accounted for by a major expansion of the BTB/kelch domain architecture.BTB/kelch proteins constitute 72 % of the kelch-repeat superfamily of H. sapiens and form three subgroups, one of which appears the most-conserved during evolution.Distinctions in propeller blade organisation between subgroups 1 and 2 were identified that could provide new direction for biochemical and functional studies of novel kelch-repeat proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA. sprag@tiscali.co.uk

ABSTRACT

Background: The kelch motif is an ancient and evolutionarily-widespread sequence motif of 44-56 amino acids in length. It occurs as five to seven repeats that form a beta-propeller tertiary structure. Over 28 kelch-repeat proteins have been sequenced and functionally characterised from diverse organisms spanning from viruses, plants and fungi to mammals and it is evident from expressed sequence tag, domain and genome databases that many additional hypothetical proteins contain kelch-repeats. In general, kelch-repeat beta-propellers are involved in protein-protein interactions, however the modest sequence identity between kelch motifs, the diversity of domain architectures, and the partial information on this protein family in any single species, all present difficulties to developing a coherent view of the kelch-repeat domain and the kelch-repeat protein superfamily. To understand the complexity of this superfamily of proteins, we have analysed by bioinformatics the complement of kelch-repeat proteins encoded in the human genome and have made comparisons to the kelch-repeat proteins encoded in other sequenced genomes.

Results: We identified 71 kelch-repeat proteins encoded in the human genome, whereas 5 or 8 members were identified in yeasts and around 18 in C. elegans, D. melanogaster and A. gambiae. Multiple domain architectures were identified in each organism, including previously unrecognised forms. The vast majority of kelch-repeat domains are predicted to form six-bladed beta-propellers. The most prevalent domain architecture in the metazoan animal genomes studied was the BTB/kelch domain organisation and we uncovered 3 subgroups of human BTB/kelch proteins. Sequence analysis of the kelch-repeat domains of the most robustly-related subgroups identified differences in beta-propeller organisation that could provide direction for experimental study of protein-binding characteristics.

Conclusion: The kelch-repeat superfamily constitutes a distinct and evolutionarily-widespread family of beta-propeller domain-containing proteins. Expansion of the family during the evolution of multicellular animals is mainly accounted for by a major expansion of the BTB/kelch domain architecture. BTB/kelch proteins constitute 72 % of the kelch-repeat superfamily of H. sapiens and form three subgroups, one of which appears the most-conserved during evolution. Distinctions in propeller blade organisation between subgroups 1 and 2 were identified that could provide new direction for biochemical and functional studies of novel kelch-repeat proteins.

Show MeSH
Related in: MedlinePlus