Trends in Cell Biology
ReviewThe kelch repeat superfamily of proteins: propellers of cell function
Section snippets
Kelch repeats form a conserved tertiary structure
The kelch motif is a segment of 44–56 amino acids in length. The sequence identity between individual kelch motifs is low: for example, 25–50% for the six motifs of Drosophila kelch or as little as 11% between individual motifs in different proteins1, 2. Multiple sequence alignment of all kelch motifs reveals eight key conserved residues, including four hydrophobic residues followed by a double glycine element, separated from two characteristically spaced aromatic residues (Fig. 1a). Because of
Biological roles of kelch-repeat proteins
Over 20 kelch-repeat molecules have now been cloned. Both the number of kelch motifs in a repeat and the position of the repeat unit within a polypeptide sequence vary widely (Table 1; Box 1)11, 12, 13, 14. Most of these molecules have also been characterized at the protein level. Collectively, their cellular distributions include the intracellular compartments, the cell surface and the extracellular milieu (Table 2; Fig. 2). Potential for functional diversity is further indicated by the
A diversity of molecular interactions
Given the structural and functional diversity within the kelch superfamily, it is not surprising that many specific binding partners have been identified (Table 2). A direct role for kelch-repeat β-propellers has been established for some of these interactions (underlined in Table 2). The clearest evidence derives from the crystal structure of galactose oxidase. A pocket on one face of the propeller coordinates a copper ion required for enzyme activity and is also the most likely site for
Conclusions and future prospects
Kelch repeat proteins have become widespread in evolution. The entire β-propeller forms a functional unit that can be found in combination with other conserved domains in the various structural subgroups within the kelch superfamily. Although there is constraint on the overall tertiary structure of β-propellers, the primary sequence identity of a kelch motif is modest. Pattern-searching strategies will probably continue to be valuable for the identification of kelch repeats in other novel
Acknowledgements
We thank Michael Way for the illustration of β-scruin, Thorsten Wolff for generously providing illustrations of NS1-BP and Shalom Avraham for communication of data prior to publication. The support of the Wellcome Trust to J.C.A. (Senior Fellowship 038284) is gratefully acknowledged. Work in the Cooley laboratory is supported by a grant from the NIH (GM52702).
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