Journal of Molecular Biology
CommunicationStructural diversity of leucine-rich repeat proteins1
Section snippets
Molecular modelling
The effectiveness of molecular modelling in improving our understanding of the sequence-structure relationship has been demonstrated for LRRs from a typical subfamily Kajava et al 1995, Bhowmick et al 1996, Weber et al 1996. The possibility of a plausible structural prediction is based primarily on two features of LRR proteins. First, as the sequences of LRRs are similar to those of RI repeats, we can assume that the 3D structural arrangement of LRR proteins is superhelical, with one side
The short LRRs occurring in bacteria
The shortest known LRRs are 20 residues long. The analysis shows that some LRR proteins consist entirely of the repeated 20-residue motif without any other domains. The outer membrane protein YopM from Yersinia pestis(Leung & Straley, 1989) has 13 such repeats, while Ipa4 and Ipa7 from Shigella flexneri(Hartman et al., 1990) have eight and six repeats, respectively. All these LRR proteins are extracellular and of Gram-negative bacterial origin. They are essential for bacterial virulence,
Plant-specific LRRs
Sequence analyses shows that some LRRs have a length similar to the typical 24-residue LRR, but their consensus sequences in the variable part differ from the typical LRR consensus (Table 1). The consensus sequence of the repeat differs from the typical 24-residue LRR in a region that corresponds to a half-turn following the conserved “β structure+Asn ladder” region. The consensus sequence of this half-turn region is Lt/sGxIP, compared to LxxLp in the typical LRR subfamily.
Most of these LRR
Cysteine-containing LRRs
In the crystal structure of RI, Asn and Cys alternate with each other at the position immediately following the β strand. Both residues form specific hydrogen bonds with the free peptide groups in the interior of the structure Kobe and Deisenhofer 1993, Kobe and Deisenhofer 1995b. Most LRR proteins have only Asn in this position on the ladder. However, the protein GRR1 from Saccharomyces cerevisiae invariably has Cys in this position (Malvar et al., 1992). The analysis reveals several other
The horseshoe curvature of LRR proteins
The conformation of the variable part of the modelled LRRs range from the polyproline II helix to the α helix. Tightly packed polyproline II helices are closer to each other (8.5 Å) compared with the α helices (10 Å). This suggests that LRR proteins from different subfamilies (at least bacterial and RI-like) may have different curvature of the overall horseshoe structure. The comparison of the energy minimised structure of bacterial LRR protein YopM and the crystal structure of RI shows that
Analysis of the cysteine-rich sequences flanking the LRR arrays
In extracellular proteins, LRR arrays are generally flanked on both N and C-terminal sides by cysteine-rich domains Schneider and Schweiger 1991, Kobe and Deisenhofer 1994. To enlarge the collection of the flanking regions I applied a sequence profile search (Bucher et al., 1996) against a recent release of the GENPEPT database. The analysis results in an identification of four different types of the C-flanking domains. The consensus sequence of the most common type of the C-flanking (CF1)
Conclusion
In conclusion, the sequence analysis allows the subdivision of the large LRR superfamily into at least six subfamilies. LRRs from the different subfamilies never occur concomitantly within one LRR protein. The structural models described here provide an explanation of this mutually exclusive relationship. In the modelled structures, the orientations of the variable non-β-structural parts of LRRs from different subfamilies are different (tilting or shifting relative to the β structure) and
Acknowledgements
I thank Dr B. Kobe for helpful discussion, constructive comments and corrections to the manuscript, and Dr K. Hofmann for valuable suggestions.
References (38)
- et al.
SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box
Cell
(1996) - et al.
Oxidation of sulfhydryl groups of ribonuclease inhibitor in epithelial cells is sufficient for its intracellular degradation
J. Biol. Chem.
(1996) - et al.
Structural and functional diversity in the leucine-rich repeat family of proteins
Prog. Biophys. Mol. Biol.
(1996) - et al.
A flexible motif search technique based on generalized profiles
Comput. Chem.
(1996) - et al.
The tomato Cf-2 disease resistance locus comprises two functional genes encoding leucine-rich repeat proteins
Cell
(1996) Standard structures in proteins
Prog. Biophys. Mol. Biol.
(1993)- et al.
Human biglycan gene. Putative promoter, intron-exon junctions, and chromosomal localization
J. Biol. Chem.
(1991) - et al.
Entry of L. monocytogenes into cells is mediated by internalin, a repeat protein reminiscent of surface antigens from Gram-positive cocci
Cell
(1991) - et al.
Modeling of the three-dimensional structure of proteins with the typical leucine-rich repeats
Structure
(1995) - et al.
The leucine-rich repeata versatile binding motif
Trends Biochem. Sci.
(1994)
Proteins with leucine-rich repeats
Curr. Opin. Struct. Biol.
The A. thaliana disease resistance gene RPS2 encodes a protein containing a nucleotide-binding site and leucine-rich repeats
Cell
Model structure of decorin and implications for collagen fibrillogenesis
J. Biol. Chem.
p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase
Cell
RPS2 of Arabidopsis thalianaa leucine-rich repeat class of plant disease resistance genes
Science
Recent changes in the GenBank On-line Service
Nucl. Acids Res.
Determination of residues important in hormone binding to the extracellular domain of the luteinizing hormone/chorionic gonadotropin receptor by site-directed mutagenesis and modeling
Mol. Endocrinol.
CHARMMa programm for macromolecular energy minimization, and dynamics calculations
J. Computat. Chem.
Crystallographic R factor refinement by molecular dynamics
Science
Cited by (0)
- 1
Edited by F. Cohen
- 2
Present address: Center for Molecular Modeling, NIH-DCRT, Bldg 12A, Room 2011, Bethesda, MD 20892, USA.