Trends in Cell Biology
Volume 10, Issue 1, 1 January 2000, Pages 17-24
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Review
The kelch repeat superfamily of proteins: propellers of cell function

https://doi.org/10.1016/S0962-8924(99)01673-6Get rights and content

Abstract

The kelch motif was discovered as a sixfold tandem element in the sequence of the Drosophila kelch ORF1 protein. The repeated kelch motifs predict a conserved tertiary structure, a β-propeller. This module appears in many different polypeptide contexts and contains multiple potential protein–protein contact sites. Members of this growing superfamily are present throughout the cell and extracellularly and have diverse activities. In this review, we discuss current information concerning the structural organization of kelch repeat proteins, their biological roles and the molecular basis of their action.

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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