Leucine-rich motifs

Figure 4.10 Consensus amino acid sequence and secondary structure of the leucine-rich motifs of type A and type B. "X" denotes any...

Leucine-rich motifs form an a/f-horseshoe fold... 

The leucine residues in this leucine-rich motif form a hydrophobic core between the P sheet and the a helices. Leucine residues 2, 5, and 7 (see Figure... 

Leucine residues 2, 5, 7, 12, 20, and 24 of the motif are invariant in both type A and type B repeats of the ribonuclease inhibitor. An examination of more than 500 tandem repeats from 68 different proteins has shown that residues 20 and 24 can be other hydrophobic residues, whereas the remaining four leucine residues are present in all repeats. On the basis of the crystal structure of the ribonuclease inhibitor and the important structural role of these leucine residues, it has been possible to construct plausible structural models of several other proteins with leucine-rich motifs, such as the extracellular domains of the thyrotropin and gonadotropin receptors. 

Figure 4.12 Schematic diagram illustrating the role of the conserved leucine residues (green) in the leucine-rich motif in stabilizing the P-loop-(x structural module. In the ribonuclease inhibitor, leucine residues 2, 5, and 7 from the P strand pack against leucine residues 17, 20, and 24 from the a helix as well as leucine residue 12 from the loop to form a hydrophobic core between the P strand and the a helix.

Upha/beta (a/p) structures are the most frequent and most regular of the pro-kein structures. They fall into three classes the first class comprises a central core of usually eight parallel p strands arranged close together like the staves pf a barrel, surrounded by a helices the second class comprises an open twisted parallel or mixed p sheet with a helices on both sides of the p sheet and Ihe third class is formed by leucine-rich motifs in which a large number of parallel p strands form a curved p sheet with all the a helices on the outside bfthis sheet. 

The horseshoe structure is formed by homologous repeats of leucine-rich motifs, each of which forms a p-loop-a unit. The units are linked together such that the p strands form an open curved p sheet, like a horseshoe, with the a helices on the outside of the p sheet and the inside exposed to solvent. The invariant leucine residues of these motifs form the major part of the hydrophobic region between the a helices and the p sheet. 

Nuclear receptors exert their different transcriptional functions through interactions with and the recruitment of co-factors to responsive promoters. Co-factors are either positive or negative regulatory proteins and are classified as co-activators, which promote, or co-repressors, which attenuate the activity of nuclear hormone receptors [46]. The molecular mechanisms that regulate the mutually exclusive interactions of the nuclear receptor with either class of co-factors have been analysed by crystallographic studies. Functional and structural studies have shown that co-activators interact with the transactivation function (AF) of nuclear hormone receptors via short, leucine-rich motifs (LXXLL) termed NR boxes , thereby transducing hormonal signals to the basal transcription machinery [47]. 

The proteoglycans in this family, which includes decorin, biglycan, lumican, and fibromodulin, are major components of the interstitial matrix produced by fibroblasts and other cells. The core proteins are small (37-45 kDa) and have several leucine-rich motifs [112] with similarity to the LH-CG receptor, thyrotropin receptor, and Drosophila proteins chaoptin and toll. Core proteins of this family characteristically undergo proteolytic processing following synthesis, with removal of an additional small peptide from the N-terminus. 

Ninkina, N. Grashchuck, M. Buchman, V.L. Davies, A.M. TrkB variants with deletions in the leucine-rich motifs of the extracellular domain. J. Biol. Chem., 272, 13019-13025 (1997)... 

Signaling by PKC is terminated by concentrations of its ligands dropping to basal levels (i.e., Ca2+ and diacylglycerol) and by dephosphorylation of the three processing sites. Dephosphorylation is controlled, in part, by a recently discovered hydrophobic phosphorylation motif phosphatase. This phosphatase, PHLPP (for PH domain Leucine-rich repeat Protein Phosphatase) dephosphorylates conventional and novel PKC isozymes, initiating their downregulation. 

Kobe, B., and Deisenhofer, J. (1994). The leucine-rich repeat A versatile binding motif. 

Leucine-rich repeats represent binding motifs found in a wide variety of both plant and mammalian proteins (Kobe and Kajava, 2001). These are involved in a multitude of protein-protein interactions. The sequence of porcine ribonuclease inhibitor, for example, displays a leucine-rich repeat (LRR) of length 27-29 residues that occurs 15 times in tandem (Fig. 9). Likewise, the family of small leucine-rich proteoglycans that includes biglycan, decorin, epiphycan, fibromodulin, keratocan, and lumican... 

The N-terminal region of NgR harbors eight canonical leucine rich repeats (LRR) that contain the LRR-signature sequence LxxLxLN/CxL. The NgR LRRs are flanked by a leucine rich repeat N-terminal subdomain (LRRNT) and a leucine rich repeat C-terminal subdomain (LRRCT), which are small protein motifs frequently found next to LRR domains. Binding studies reveal that the leucine rich domains are necessary and sufficient for ligand recognition (Fournier et al., 2002). 

The extracellular domain of Trk receptors is made up of three leucine-rich 24 residue motifs flanked on either side by a cysteine cluster (Cl is on the outer side and C2 is in the inner side), followed by two immunoglobulin (Ig)-like domains and a single transmembrane domain. The cytoplasmic domain of Trk receptors contains several tyrosine motifs (Huang and Reichardt, 2003). The major ligand binding site on Trk receptors is located in the region proximal to the Ig-... 

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