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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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Relationships between human BTB/kelch proteins. The amino acid sequences of the 38 full-length human BTB/kelch proteins predicted to contain six-bladed β-propellers were aligned in CLUSTALW and are presented in Phylip Drawgram for A) full-length sequences; B) kelch-repeat domains only; C) BTB domains only, with shade codes for the three identified subgroups as indicated. Asterisk in panel A indicate known actin-binding BTB/kelch proteins. Panel B shows the robust grouping of a set of sequences from subgroup 2, termed subgroup 2A.
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Figure 2: Relationships between human BTB/kelch proteins. The amino acid sequences of the 38 full-length human BTB/kelch proteins predicted to contain six-bladed β-propellers were aligned in CLUSTALW and are presented in Phylip Drawgram for A) full-length sequences; B) kelch-repeat domains only; C) BTB domains only, with shade codes for the three identified subgroups as indicated. Asterisk in panel A indicate known actin-binding BTB/kelch proteins. Panel B shows the robust grouping of a set of sequences from subgroup 2, termed subgroup 2A.

Mentions: The unexpectedly large number of BTB/kelch proteins encoded in the human genome prompted us to study this group in more detail, with the aim of identifying structural subgroups that might also represent functional subsets. The 38 full-length sequences that contained single BTB domains and predicted six-bladed β-propellers were aligned according to sequence similarity in CLUSTALW and viewed as neighbourhood-joining trees. Alignment of the full-length sequences revealed three subgroups of approximately equal size, which we termed subgroups 1 to 3 (Fig. 2A). When the same analysis was performed with the kelch domains alone, the same grouping was apparent for subgroup 1 and a substantial proportion of subgroup 2, termed subgroup 2A (Fig. 2B). In an alignment of the BTB domains only, subgroups 1 and 2 were maintained for the majority of sequences (Fig. 2C). Unrooted trees produced by a separate method for alignment based on maximum parsimony analysis of sequences, PROTPARS, did not support subgroup 3 but consistently demonstrated the relationship of the sequences in subgroups 1 and 2A (data not shown). We focused on these robustly-related kelch-repeat sequences in subgroups 1 and 2A, for a closer analysis of the kelch-repeat domains.


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

Prag S, Adams JC - BMC Bioinformatics (2003)

Relationships between human BTB/kelch proteins. The amino acid sequences of the 38 full-length human BTB/kelch proteins predicted to contain six-bladed β-propellers were aligned in CLUSTALW and are presented in Phylip Drawgram for A) full-length sequences; B) kelch-repeat domains only; C) BTB domains only, with shade codes for the three identified subgroups as indicated. Asterisk in panel A indicate known actin-binding BTB/kelch proteins. Panel B shows the robust grouping of a set of sequences from subgroup 2, termed subgroup 2A.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC222960&req=5

Figure 2: Relationships between human BTB/kelch proteins. The amino acid sequences of the 38 full-length human BTB/kelch proteins predicted to contain six-bladed β-propellers were aligned in CLUSTALW and are presented in Phylip Drawgram for A) full-length sequences; B) kelch-repeat domains only; C) BTB domains only, with shade codes for the three identified subgroups as indicated. Asterisk in panel A indicate known actin-binding BTB/kelch proteins. Panel B shows the robust grouping of a set of sequences from subgroup 2, termed subgroup 2A.
Mentions: The unexpectedly large number of BTB/kelch proteins encoded in the human genome prompted us to study this group in more detail, with the aim of identifying structural subgroups that might also represent functional subsets. The 38 full-length sequences that contained single BTB domains and predicted six-bladed β-propellers were aligned according to sequence similarity in CLUSTALW and viewed as neighbourhood-joining trees. Alignment of the full-length sequences revealed three subgroups of approximately equal size, which we termed subgroups 1 to 3 (Fig. 2A). When the same analysis was performed with the kelch domains alone, the same grouping was apparent for subgroup 1 and a substantial proportion of subgroup 2, termed subgroup 2A (Fig. 2B). In an alignment of the BTB domains only, subgroups 1 and 2 were maintained for the majority of sequences (Fig. 2C). Unrooted trees produced by a separate method for alignment based on maximum parsimony analysis of sequences, PROTPARS, did not support subgroup 3 but consistently demonstrated the relationship of the sequences in subgroups 1 and 2A (data not shown). We focused on these robustly-related kelch-repeat sequences in subgroups 1 and 2A, for a closer analysis of the kelch-repeat domains.

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