ReviewThe leucine-rich repeat as a protein recognition motif
Introduction
Repeating amino acid segments are increasingly recognized as important components of proteins, particularly eukaryotic ones 1., 2.. A subset of repeating motifs correspond to structural units that assemble in a superhelical fashion and form solenoid protein structures 3., 4•., 5•..
One such repeating motif was first recognized in the leucine-rich α2-glycoprotein and was termed the leucine-rich repeat (LRR) [6]. An ever-increasing number of proteins with diverse functions have subsequently revealed tandem arrays of related amino acid motifs (reviewed in 3., 7., 8., 9., 10.). Most but not all of these proteins are eukaryotic and most if not all appear to be involved in protein–protein recognition processes. The LRRs are generally 20–29 residues long and contain a conserved 11-residue segment with the consensus sequence LxxLxLxxN/CxL (xcan be any amino acid and L positions can also be occupied by valine, isoleucine and phenylalanine). The crystal structure of ribonuclease inhibitor (RI) yielded the first insight into the 3D structural arrangement of LRRs [11] and, soon thereafter, crystal structures of complexes of RI with its ligands provided the first structural views revealing how the LRR structure is used as a protein recognition motif 12., 13.. This structural information also formed the basis of numerous attempts to model LRR proteins and their ligand complexes 10., 14., 15., 16., 17., 18., 19., 20., 21., 22., 23..
In the past few years, a number of new 3D structures of LRR proteins have been determined. In this review, we focus on this novel structural information and its implications for understanding the structural and functional attributes of LRR proteins.
Section snippets
New structures of leucine-rich repeat proteins
The structure of porcine RI showed that LRRs corresponded to structural units, each consisting of a β strand and an α helix connected by loops [11]. The structural units were arranged so that all the strands and helices were parallel to a common axis, resulting in a nonglobular, horseshoe-shaped molecule with a curved parallel β sheet lining the inner circumference of the horseshoe and the helices flanking the outer circumference (Fig. 1a).
The structure of RI explained the conservation of
Subfamilies of leucine-rich repeat proteins
Sequence analyses of LRR proteins suggested the existence of several different subfamilies of LRRs 9., 10., 14., 26., 35.. The most recent classifications reveal at least seven distinct subfamilies (Table 2, [10]; AV Kajava, B Kobe, unpublished data). The significance of this classification is that repeats from different subfamilies never occur simultaneously in the same protein and have most probably evolved independently. The known structure of RI allowed the construction of 3D models of LRRs
Modeling of leucine-rich repeat structures
The available structural information can be used to construct models of novel LRR proteins. No experimental information is available yet for the structures of the typical, plant-specific and TpLRR subclasses.
However, analyses suggest that quite reliable models for all the major classes can be obtained using the available information ([10]; AV Kajava, B Kobe, unpublished data). In particular, a comparison of models constructed solely on the basis of the structure of RI 10., 14. with the new
Functions of leucine-rich repeat proteins
LRR proteins participate in many biologically important processes, such as hormone–receptor interactions, enzyme inhibition, cell adhesion and cellular trafficking. A number of recent studies revealed the involvement of LRR proteins in early mammalian development [40], neural development [41], cell polarization [42], regulation of gene expression [43] and apoptosis signaling [44]. It was shown that LRR domains may be critical to the morphology and dynamics of the cytoskeleton 31••., 45.. In all
Conclusions
The identification of new LRR proteins through genome sequencing projects and the functional characterization of new and old LRR proteins emphasize the important roles LRR domains play in various cellular processes and suggest that the major function of LRR domains is to facilitate protein–protein interactions. The new structural information strongly suggests that LRR proteins from all the major subfamilies have related structures and facilitates reliable modeling of such proteins with unknown
Update
Ward and Garrett [47] recently suggested, based on sequence and structure comparisons, that pectate lyase and the L domains of members of the insulin receptor and epidermal growth factor receptor families are members of the LRR superfamily. We discussed above how these structures and the corresponding repeat profiles differ from the LRR proteins.
The structure of a larger fragment of InlB and an equivalent fragment of the related InlH have recently been reported [48]. The structures show that
Acknowledgements
We thank David S Waugh and co-workers for sharing unpublished data on the YopM protein. BK is a Wellcome Senior Research Fellow in Medical Science in Australia.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:• of special interest•• of outstanding interest
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