Structural analysis of leucine-rich-repeat variants in proteins associated with human diseases

Abstract

A number of human diseases have been shown to be associated with mutation in the genes encoding leucine-rich-repeat (LRR)-containing proteins. They include 16 different LRR proteins. Mutations of these proteins are associated with 19 human diseases. The mutations occur frequently within the LRR domains as well as their neighboring domains, including cysteine clusters. Here, based on the sequence analysis of the LRR domains and the known structure of LRR proteins, we describe some features of different sequence variants and discuss their adverse effects. The mutations in the cysteine clusters, which preclude the formation of sulfide bridges or lead to a wrong paring of cysteines in extracellular proteins or extracellular domains, occur with high frequency. In contrast, missense mutations at some specific positions in LRRs are very rare or are not observed at all.

A new structural model of the acid-labile subunit: pathogenetic mechanisms of short stature-causing mutations

“…The N-and C-termini are enriched in proline residues and contain several potential S-S bonds, whose function is likely to be the capping of the LRR hydrophobic core. Shielding of the LRR core by N and C caps is a common feature in LRR proteins and, similar to what is observed in ALS, the N and C caps of extracellular LRR proteins often contain clusters of cysteines, which form disulphide bridges (Buchanan & Gay 1996, Matsushima et al 2005. Three of the putative S-S bridges identified by our analysis are conserved features in the templates used for ALS model prediction.…”

“…The LRR units of ALS and of the other members of the LRR family form a characteristic arc or horseshoe. The LRR arc is characterised by three geometrical parameters that are derived from the solved protein structure: the tilt angle of the parallel b-strand direction turn (q), the mean rotation angle about the central axis relating one b-strand to the next (4) and the inner radius of the arc (R) (Matsushima et al 2005). Duplication Leu 437_Leu439 alters the formation of the b-strand motif in LRR17, as residues 438 and 439 contribute to the formation of the highly conserved b-strand of the LRR (Enkhbayar et al 2004).…”

Primate segmental duplication creates novel promoters for theLRRC37gene family within the 17q21.31 inversion polymorphism region

“…Toll-like receptors (TLRs) are, for example, single membrane spanning proteins whose extracellular domains are composed of LRRs, which recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides (LPS), single-stranded RNA, and flagellin (Hoshino et al 1999;Barton and Medzhitov 2002). LRR-containing proteins, such as Densin-180, Erbin, NGL, and SALM, have also been implicated in neuron-specific functions such as axonal guidance and neuronal migration and have been shown to localize to neuronal synapses (for review in detail, see Matsushima et al 2005Matsushima et al , 2007Ko and Kim 2007).…”

The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

“…LRRs are 20-29 amino-acid (aa) motifs that contain the conserved 11-aa sequence, LxxLxLxxN/ CxL, where x is any amino acid, and leucines and asparagine can be replaced with other hydrophobic residues (Kobe and Kajava, 2001). This domain is usually found as a tandem array of a few (or more) individual motifs (Matsushima et al, 2005). The structures of several LRR-containing proteins, including ribonuclease inhibitor and Toll-like receptors (TLRs) (Jin and Lee, 2008;Kobe and Deisenhofer, 1993), have been resolved.…”

“…Mounting evidence from invertebrate systems shows that extracellular LRR proteins control key phases of neuron development and neural circuit formation including axon guidance, target-cell recognition, and synapse formation. The importance of these proteins is further emphasized by the fact that several LRR proteins have been associated with human neurodevelopmental and neuropsychiatric disorders (Matsushima et al, 2005).…”