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<scene name='82/829346/Lrrtm2/3'>LRRTM2</scene> is a transmembrane protein that can be found in human neurons. It functions as postsynaptic organizers that induce excitatory synapses. LRRTM2 is prominently expressed in deep layers (hippocampal neurons mostly), rather than superficial layers, of the cerebral cortex. LRRTM2 specifically localizes in excitatory synapses, and not in inhibitory synapses. In addition, LRRTMs interact with neurexins[http://proteopedia.org/wiki/index.php/Neurexin]to bridge the synaptic cleft. | <scene name='82/829346/Lrrtm2/3'>LRRTM2</scene> is a transmembrane protein that can be found in human neurons. It functions as postsynaptic organizers that induce excitatory synapses. LRRTM2 is prominently expressed in deep layers (hippocampal neurons mostly), rather than superficial layers, of the cerebral cortex. LRRTM2 specifically localizes in excitatory synapses, and not in inhibitory synapses. In addition, LRRTMs interact with neurexins[http://proteopedia.org/wiki/index.php/Neurexin]to bridge the synaptic cleft. | ||
== Structural highlights == | == Structural highlights == | ||
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The X-ray structure of LRRTM2 reveals that this transmembrane protein is composed of 3 main domains: a N-terminal leucine rich repeat domain which is extracellular, a single transmembrane domain and a C-terminal cytoplasmic region. The protein is composed of 516 amino acids. | The X-ray structure of LRRTM2 reveals that this transmembrane protein is composed of 3 main domains: a N-terminal leucine rich repeat domain which is extracellular, a single transmembrane domain and a C-terminal cytoplasmic region. The protein is composed of 516 amino acids. | ||
[[Image:LRRTM2 details.png| | [[Image:LRRTM2 details.png|500px|left]] | ||
'''<scene name='82/829346/Lrrtm2/5'>N-term fixation domain</scene>''' | '''<scene name='82/829346/Lrrtm2/5'>N-term fixation domain</scene>''' | ||
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'''LRRTMs Family
''' | '''LRRTMs Family
''' | ||
All four members of the human LRRTM family are highly similar in their LRR domains with >55% sequence identity. But only LRRTM1 and LRRTM2 have been extensively studied in the context of the interaction with | All four members of the human LRRTM family are highly similar in their LRR domains with >55% sequence identity. But only LRRTM1 and LRRTM2 have been extensively studied in the context of the interaction with neurexins[http://proteopedia.org/wiki/index.php/Neurexin]. This is due to the fact that some critical residues for binding with <scene name='82/829346/Beta-neurexin_1/2'>Nrxn1β</scene> have been replaced in LRRTM3 and LRRTM4, such as <scene name='82/829346/Glu_348/1'>Glu348</scene>, <scene name='82/829346/Asp_352/1'>Asp352</scene>, and <scene name='82/829346/Phe_357/2'>Phe357</scene>. | ||
The replacement of Glu348 by Val in LRRTM3 is likely to prevent of the interaction between Ca2+ and Nrxn1β. It is possible that other specific residue(s) of LRRTM3/4 may also prevent the binding. | The replacement of Glu348 by Val in LRRTM3 is likely to prevent of the interaction between Ca2+ and Nrxn1β. It is possible that other specific residue(s) of LRRTM3/4 may also prevent the binding. | ||
'''Ligands''' | '''Ligands''' | ||
Neurexins (Nrxns) [http://proteopedia.org/wiki/index.php/Neurexin]is a family of the presynaptic organizer which interact with several postsynaptic organizers such as LRRTM2. | |||
There are three Neurexin genes in vertebrates, each corresponding to a different promoter type. Neurexins are characterized by their laminin-neurexin-sex hormone (LNS) domains. ︎ <scene name='82/829346/Neurexin_1_alpha/1'>α-neurexins</scene> have six whereas ︎<scene name='82/829346/Beta-neurexin_1/2'>β-neurexins</scene> have a single LNS domain. The α-helical conformation causes severe steric hindrance with the bound LRRTM2, whereas the β-stranded conformation causes no obvious steric hindrance. | |||
The structure of the complex <scene name='82/829346/Complex/1'>Nrxn1β–LRRTM2</scene>[http://proteopedia.org/wiki/index.php/5z8y]is being determined by co-crystallisation. A mutation from His 355 to Ala 355 without affecting the complex structure is necessary to maintain the stability of the crystal. | The structure of the complex <scene name='82/829346/Complex/1'>Nrxn1β–LRRTM2</scene>[http://proteopedia.org/wiki/index.php/5z8y]is being determined by co-crystallisation. A mutation from His 355 to Ala 355 without affecting the complex structure is necessary to maintain the stability of the crystal. | ||
PSD-95 [http://proteopedia.org/wiki/index.php/1tq3] is a postsynaptic scaffolding protein playing a role in the regulation of the expression of the genes coding for AMPA receptors. This protein also play a role in the translocation of LRRTM2 after the translation. | |||
'''Other synaptic organisers''' | '''Other synaptic organisers''' | ||
Neuroligins (NLs)[http://proteopedia.org/wiki/index.php/3vkf] | |||
LRRTM2 bind to Neurexins 1, 2 and 3 ︎and ︎a variant region at splice site 4 in the LNS. As the variant region lacking a 30 amino acid insert (-S4), LRRTM2 cannot induce presynaptic differentiation in neurons. On the contrary, <scene name='82/829346/Neurologin-neurexin/1'>Neuroligin1</scene> binds to Neurexins 1, 2, and 3, has a higher affinity with Neurexin 1 (-S4) than with Neurexin 1 (+S4). As both Neuroligins and LRRTMs bind to Neurexins, Neuroligins can compensate for reduced LRRTMs functions. Those proteins works in a summative way to enhance the recruitment of presynaptic protein. | |||
== Disease == | |||
Autism Spectrum Disorders (ASDs) is a broad group of various autism disorders such as Asperger, Rett and others development disorders. It is also associated to schizophrenia and Tourette Syndrome. An important number of proteins are implicated in those diseases and only a few are actually been proven to be linked to those disorders. Both neurexins and LRR proteins are good candidates. It have been shown that mutation in Nrxn1 can lead to modification of the LNS fixation site (part that binds to LRRTM2) resulting in autism. It was also demonstrated that mutations in LRR lead to hereditary lateral temporal epilepsy and Parkinson. | |||
A deletion (240 kb) at 5q31 chromosomal region containing LRRTM2 has been shown to be related to intellectual disability and developmental delay. | |||
Some studies also show that LRRTM2 is also related to bipolar disorder. | |||
== References == | == References == | ||
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https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.13159 | https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.13159 | ||
https://www.rcsb.org/structure/5Z8X | https://www.rcsb.org/structure/5Z8X | ||
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066302/pdf/nihms258120.pdf | |||
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913944/pdf/2040-2392-1-7.pdf | |||
https://espace.library.uq.edu.au/view/UQ:313747 | |||
