The leucine-rich repeat is a widespread structural motif of 20-30 amino acids with a characteristic repetitive sequence pattern rich in leucines. Leucine-rich repeat domains are built from tandems of two or more repeats and form curved solenoid structures that are particularly suitable for protein-protein interactions. Thousands of protein sequences containing leucine-rich repeats have been identified by automatic annotation methods. Three-dimensional structures of leucine-rich repeat domains determined to date reveal a degree of structural variability that translates into the considerable functional versatility of this protein superfamily. As the essential structural principles become well established, the leucine-rich repeat architecture is emerging as an attractive framework for structural prediction and protein engineering. This review presents an update of the current understanding of leucine-rich repeat structure at the primary, secondary, tertiary and quaternary levels and discusses specific examples from recently determined three-dimensional structures.

Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX. Although bleeding associated with FXI deficiency is relatively mild, there has been resurgence of interest in FXI because of studies indicating it makes contributions to thrombosis and other processes associated with dysregulated coagulation. FXI is an unusual dimeric protease, with structural features that distinguish it from vitamin K-dependent coagulation proteases. The recent availability of crystal structures for zymogen FXI and the FXIa catalytic domain have enhanced our understanding of structure-function relationships for this molecule. FXI contains 4 "apple domains" that form a disk structure with extensive interfaces at the base of the catalytic domain. The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets. Analyses of missense mutations associated with FXI deficiency have provided additional clues to localization of ligand-binding sites on the protein surface. Together, these data will facilitate efforts to understand the physiology and pathology of this unusual protease, and development of therapeutics to treat thrombotic disorders. (Blood. 2010; 115(13):2569-2577) IntroductionFactor XI (FXI) is the zymogen of a blood coagulation protease, factor XIa (FXIa), that contributes to hemostasis through activation of factor IX (FIX; Figure 1). [1][2][3] The protein is a 160-kDa disulfide-linked dimer of identical 607 amino acid subunits, each containing 4 90-or 91-amino acid repeats called apple domains (A1 to A4 from the N-terminus) and a C-terminal trypsin-like catalytic domain. [3][4][5][6][7] The structure is distinctly different from those of the well-characterized vitamin K-dependent coagulation proteases. 1 FXI circulates in blood as a complex with high molecular weight kininogen (HK). 8 Prekallikrein (PK), the zymogen of the protease ␣-kallikrein, is a monomeric homolog of FXI with the same domain structure 9,10 that also circulates in complex with HK. 11 A recent analysis of vertebrate genomes confirmed that FXI and PK are products of a duplication event during mammalian evolution. 12 The ancestral predecessor is also a protease with 4 apple domains, but its functional properties have not been studied. 12 In the cascade/waterfall models of coagulation that are the basis for the activated partial thromboplastin time (aPTT) assay, FXI activation by FXIIa initiates fibrin formation (Figure 1). 1 However, newer schemes do not assign FXI a role in early fibrin generation, based largely on the observation that FXI deficiency causes relatively mild bleeding. [1][2][3] FXIa is now postulated to be part of a feedback loop that sustains thrombin generation through FIX activation to consolidate coagulation (Figure 1). [13][14][15] This appears to be particularly important in tissues with robust fibrinolytic acti...

Decorin is a ubiquitous extracellular matrix proteoglycan with a variety of important biological functions that are mediated by its interactions with extracellular matrix proteins, cytokines, and cell surface receptors. Decorin is the prototype of the family of small leucine-rich repeat proteoglycans and proteins (SLRPs), characterized by a protein core composed of leucine-rich repeats (LRRs), flanked by two cysteine-rich regions. We report here the crystal structure of the dimeric protein core of decorin, the best characterized member of the SLRP family. Each monomer adopts the curved solenoid fold characteristic of LRR domains, with a parallel ␤-sheet on the inside interwoven with loops containing short segments of ␤-strands, 310 helices, and polyproline II helices on the outside. Two main features are unique to this structure. First, decorin dimerizes through the concave surfaces of the LRR domains, which have been implicated previously in protein-ligand interactions. The amount of surface buried in this dimer rivals the buried surfaces of some of the highest-affinity macromolecular complexes reported to date. Second, the C-terminal region adopts an unusual capping motif that involves a laterally extended LRR and a disulfide bond. This motif seems to be unique to SLRPs and has not been observed in any other LRR protein structure to date. Possible implications of these features for decorin ligand binding and SLRP function are discussed.