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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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Multiple sequence alignment of subgroup 2A human BTB/kelch proteins. The kelch-repeat domains of the 10 subgroup 2A BTB/kelch proteins were aligned in CLUSTALW to generate a 50 % identity threshold level consensus sequence. The alignments are presented for each repeat, with the repeat unit assigned according to the 1GOF structure. The four β-strands in each repeat are color-coded as in Fig. 1A. Alignments are presented in Boxshade: black shading indicates identical amino acids, grey shading indicates similar amino acids and white background indicates unrelated amino acids.
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Figure 4: Multiple sequence alignment of subgroup 2A human BTB/kelch proteins. The kelch-repeat domains of the 10 subgroup 2A BTB/kelch proteins were aligned in CLUSTALW to generate a 50 % identity threshold level consensus sequence. The alignments are presented for each repeat, with the repeat unit assigned according to the 1GOF structure. The four β-strands in each repeat are color-coded as in Fig. 1A. Alignments are presented in Boxshade: black shading indicates identical amino acids, grey shading indicates similar amino acids and white background indicates unrelated amino acids.

Mentions: CLUSTALW multiple sequence alignment of the kelch-repeat domains from each of subgroups 1 and 2A demonstrated distinctive features in terms of repeat organisation. In both subgroups (Fig. 3 and Fig. 4), the intrablade loop between β-strands 2 and 3 (the 2–3 loop, Fig. 5A) and the interblade 4–1 loop were major sources of variation within the repeats with regard to their length and primary structure. In the context of an intact β-propeller domain, the 1–2 and 3–4 loops protrude above one face of the β-sheets and the 2–3 loop protrudes from the opposite face (Fig. 5A). The 4–1 loop lies either on the same face as the 2–3 loop, or may be positioned more closely to the β-sheet core of the propeller (Fig. 5). In subgroup 1, the longest 2–3 loops were found in repeats 1, 5 and 6, with shorter loops in blades 2, 3 and 4. The longest 4–1 loop were that between repeats 5 and 6 (Fig. 3). In the context of a β-propeller, this suggests that the side of the propeller formed by repeats 5, 6 and 1 may be particularly involved in protein interactions (see Fig. 1C). In subgroup 2A, the longest 2–3 loops were those in repeats 1 and 2, repeats 4 and 5 had intermediate 2–3 loops and repeats 3 and 6 contained the shortest 2–3 loops. The longest 4–1 loops were those between repeats 1 and 2, and repeats 3 and 4 (Fig. 4). This suggests that there is a different organisation of binding sites in subgroup 2A β-propellers, with perhaps two binding faces formed by repeats 1 and 2, and repeats 4 and 5. At the level of individual sequences, there were also specific examples of variation from the standard repeat organisation that could be of functional importance for individual proteins. For example, NP_695002 in subgroup 2A has an unusually long and highly charged 3–4 loop in repeat 1 and XP_ 040383 has a long 3–4 loop in repeat 4 (Fig. 4).


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

Prag S, Adams JC - BMC Bioinformatics (2003)

Multiple sequence alignment of subgroup 2A human BTB/kelch proteins. The kelch-repeat domains of the 10 subgroup 2A BTB/kelch proteins were aligned in CLUSTALW to generate a 50 % identity threshold level consensus sequence. The alignments are presented for each repeat, with the repeat unit assigned according to the 1GOF structure. The four β-strands in each repeat are color-coded as in Fig. 1A. Alignments are presented in Boxshade: black shading indicates identical amino acids, grey shading indicates similar amino acids and white background indicates unrelated amino acids.
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Related In: Results  -  Collection

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

Figure 4: Multiple sequence alignment of subgroup 2A human BTB/kelch proteins. The kelch-repeat domains of the 10 subgroup 2A BTB/kelch proteins were aligned in CLUSTALW to generate a 50 % identity threshold level consensus sequence. The alignments are presented for each repeat, with the repeat unit assigned according to the 1GOF structure. The four β-strands in each repeat are color-coded as in Fig. 1A. Alignments are presented in Boxshade: black shading indicates identical amino acids, grey shading indicates similar amino acids and white background indicates unrelated amino acids.
Mentions: CLUSTALW multiple sequence alignment of the kelch-repeat domains from each of subgroups 1 and 2A demonstrated distinctive features in terms of repeat organisation. In both subgroups (Fig. 3 and Fig. 4), the intrablade loop between β-strands 2 and 3 (the 2–3 loop, Fig. 5A) and the interblade 4–1 loop were major sources of variation within the repeats with regard to their length and primary structure. In the context of an intact β-propeller domain, the 1–2 and 3–4 loops protrude above one face of the β-sheets and the 2–3 loop protrudes from the opposite face (Fig. 5A). The 4–1 loop lies either on the same face as the 2–3 loop, or may be positioned more closely to the β-sheet core of the propeller (Fig. 5). In subgroup 1, the longest 2–3 loops were found in repeats 1, 5 and 6, with shorter loops in blades 2, 3 and 4. The longest 4–1 loop were that between repeats 5 and 6 (Fig. 3). In the context of a β-propeller, this suggests that the side of the propeller formed by repeats 5, 6 and 1 may be particularly involved in protein interactions (see Fig. 1C). In subgroup 2A, the longest 2–3 loops were those in repeats 1 and 2, repeats 4 and 5 had intermediate 2–3 loops and repeats 3 and 6 contained the shortest 2–3 loops. The longest 4–1 loops were those between repeats 1 and 2, and repeats 3 and 4 (Fig. 4). This suggests that there is a different organisation of binding sites in subgroup 2A β-propellers, with perhaps two binding faces formed by repeats 1 and 2, and repeats 4 and 5. At the level of individual sequences, there were also specific examples of variation from the standard repeat organisation that could be of functional importance for individual proteins. For example, NP_695002 in subgroup 2A has an unusually long and highly charged 3–4 loop in repeat 1 and XP_ 040383 has a long 3–4 loop in repeat 4 (Fig. 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