SLITRK1

4RCA, 4RCW11479876965ENSG00000178235ENSMUSG00000075478Q96PX8Q810C1NM_052910NM_001281503NM_199065NP_001268432NP_443142NP_951020SLITRK1 ('SLIT and NTRK-like family, member 1') is a human gene that codes for a transmembrane and signalling protein that is part of the SLITRK gene family, which is responsible for synapse regulation and presynaptic differentiation in the brain. Expression of the gene has been linked to early formation of excitatory synapses through binding with receptor tyrosine phosphatase PTP (LAR-RPTP). Various studies over the years have linked mutations in the gene to conditions on the OCD spectrum, Tourette syndrome and trichotillomania, however the mutations in the genome itself vary greatly between individuals, with most mutations observed being hard to find in repeat studies. SLITRK1 ('SLIT and NTRK-like family, member 1') is a human gene that codes for a transmembrane and signalling protein that is part of the SLITRK gene family, which is responsible for synapse regulation and presynaptic differentiation in the brain. Expression of the gene has been linked to early formation of excitatory synapses through binding with receptor tyrosine phosphatase PTP (LAR-RPTP). Various studies over the years have linked mutations in the gene to conditions on the OCD spectrum, Tourette syndrome and trichotillomania, however the mutations in the genome itself vary greatly between individuals, with most mutations observed being hard to find in repeat studies. Members of the SLITRK family, such as SLITRK1, are integral membrane proteins with 2 N-terminal leucine-rich repeat (LRR) domains similar to those of SLIT proteins (see SLIT1; MIM 603742). Most SLITRKs, but not SLITRK1, also have C-terminal regions that share homology with neurotrophin receptors (see NTRK1; MIM 191315). SLITRKs are expressed predominantly in neural tissues and have neurite-modulating activity (Aruga et al., 2003). The gene for SLITRK1 is located on chromosome 13q31.1. The gene is expressed only in the brain of humans. The mRNA can differ from alternative splicing, and contains domains for the extracellular matrix as well as for the LRRs. Mice contain an ortholog of the gene called Slitrk1. SLITRK1 contains 2 horseshoe shaped leucine rich repeat domains (LRRs) in its extracellular domain which are vital to its function. The LRRs have 6 modules each and are connected by a 70-90 amino acid loops. LRR1 is a more conserved sequence and is present as a dimer while LRR2 is a monomer and has a more variable sequence. The conserved sequence of LRR1 contains critical binding pockets and specific charged residues that are important for it to carry out its function of binding to LAR-RPTPs on the N-terminus. Both LRR sequences are randomly positioned on the protein and contain variable linker regions. The protein also contains a short intracellular domain, but lacks a tyrosine phosphorylation motif which is present in other SLITRK genes. SLITKR1 is highly expressed in the central nervous system. It plays a critical part in regulating synapse formation between hippocampal neurons and in differentiation of synapses, helping in neuronal outgrowth. It is expressed during embryonic stages and postnatally but expression decreases over time and is localized to the postsynaptic membrane. Overexpression of SLITKR1 promotes postsynaptic differentiation for excitatory and inhibitory synapses, but because of the localization only excitatory synapses are affected. Inhibition of SLITKR1 only reduces differentiation of excitatory synapses because of this. Since they lack tyrosine phosphorylation motifs, SLITKR1 binds to LAR-RPTP through its LRR1 region in order to differentiate synapses. The LRR2 domain's function is not clearly understood yet but it is hypothesised that it is for dimerization to the cell surface. LAR-RPTP binds to the LRR1 region through its PTPδ Ig region, with 3 separate binding sites in a 1:1 binding ratio. Ig1 binds through electrostatic and hydrophobic interactions, Ig2 binds through ionic and hydrogen bonds, and Ig2 binds through hydrogen bonding. The unique properties on the concave surface are what determine which LAR-RPTP binds to it. If the proper LAR-RPTP is not bound to the LRR1 then synapse formation cannot occur, but bonding can still occur. Once they are bound properly, the complex is sufficient for synapse differentiation. Point mutations in the LRR1 region impaired differentiation as well but not binding. The SLITRK1 gene 'is not a major risk gene for the majority of individuals' with Tourette syndrome (TS), according to a 2009 review, although its study can help contribute to our understanding of TS. Rare variants in SLITRK1 may lead to TS, and mutations in non-coding regions of SLITRK1 may also play a part, but further research needs to be done before any conclusions can be drawn.