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| - | <scene name='82/829346/Lrrtm2/ | + | <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 == | ||
| - | <StructureSection load= | + | <StructureSection load=5z8x> |
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| - | The X-ray structure of | + | 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|500px|left]] | |
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| + | '''<scene name='82/829346/Lrrtm2/5'>N-term fixation domain</scene>''' | ||
| - | The N-terminal signal peptide is long of 33 amino. The extracellular domain contains 399 amino acids organized in 2 cysteine-rich domains (LRRNT and LRRCT) and 10 leucine rich domains (LRR). Each LRR domain is composed of 21 amino acids containing the conserved 11-aa sequence, LxxLxLxxN/ CxL, where x is any amino acid, and | + | The N-terminal signal peptide is long of 33 amino. The extracellular domain contains 399 amino acids organized in 2 cysteine-rich domains (<scene name='82/829346/Lrrnt/1'>LRRNT</scene> and <scene name='82/829346/Lrrct/1'>LRRCT</scene>) and <scene name='82/829346/Lrr/2'>10 leucine rich domains</scene> (LRR). Each LRR domain is composed of 21 amino acids containing the conserved 11-aa sequence, LxxLxLxxN/ CxL, where x is any amino acid, and <scene name='82/829346/Leucine/1'>leucine</scene> and asparagine can be replaced with other hydrophobic residues. The leucine rich repeat domain forms a convex structure stabilized by a <scene name='82/829346/Phe/1'>Phe</scene> spine. The concave surface is composed of a continuous <scene name='82/829346/Beta_sheets/1'>β-sheet</scene>, which provides an effective ligand-binding site, whereas the convex surface consists of <scene name='82/829346/Alpha_helix/1'>α-helices</scene>, which affect the curvature of the LRR domain. |
| - | The N-terminal domain allows for the fixation of Nrxns which | + | The N-terminal domain allows for the fixation of neurexins (Nrxns) [http://proteopedia.org/wiki/index.php/Neurexin] which bind to the concave surface of the LRR1-LRR5 part of the protein. This fixation is mediated by calcium ions which interacts with the <scene name='82/829346/Asp_144_and_212/1'>Asp144 and Asp212</scene> of LRRTMT2. It was also observed that <scene name='82/829346/Glu_348/1'>LRRTM2 Glu348</scene> interacts with Ca2+ through a water molecule. In top of the Ca2+ mediated interaction, there is the formation of a hydrogen bound between the <scene name='82/829346/Asp_352/1'>Asp352</scene> of LRRTM2 and the Arg206 of Nrxns as well as hydrophobic interactions between the LRRTM2 <scene name='82/829346/Phe_357/1'>Phe357</scene> and Nrxns Leu208. |
The fixation of Nrxns doesn’t change the conformation of the protein aside from Glu348 flipping toward the calcium ions. | The fixation of Nrxns doesn’t change the conformation of the protein aside from Glu348 flipping toward the calcium ions. | ||
| - | + | '''Trans Membrane domain''' | |
The transmembrane domain is a 21 amino acid long helical domain. | The transmembrane domain is a 21 amino acid long helical domain. | ||
| - | + | '''C-term fixation domain''' | |
| - | The cytoplasmic domain contains 73 amino acids. It has been shown that the deletion of 55 residues from the C-terminal domain leads to abnormal intracellular trafficking pathway. This results in LRRTM2 being present | + | The cytoplasmic domain contains 73 amino acids. It has been shown that the deletion of 55 residues from the C-terminal domain leads to abnormal intracellular trafficking pathway. This results in LRRTM2 being present everywhere in the cell. This domain also contains a PSD consensus cytoplasmic binding domain (ECEV) which binds PSD-95 [http://proteopedia.org/wiki/index.php/1tq3] (postsynaptic scaffolding protein) |
| - | This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. | ||
</StructureSection> | </StructureSection> | ||
| + | |||
== Function == | == Function == | ||
| - | == Disease == | ||
| - | + | LRRTM2 protein play a key role in the regulation of the synaptic fonctions and development by interracting with various proteins both inside and outside the neuron cell. | |
| - | + | ||
| - | == Relevance == | ||
| - | ''' | + | '''Interaction with extracellular proteins''' |
| - | + | On the N-term fixation site, LRRTM2 binds specifically to Neurexin1 <scene name='82/829346/Neurexin_1_alpha/1'>α</scene> and <scene name='82/829346/Beta-neurexin_1/2'>β</scene> [http://proteopedia.org/wiki/index.php/Neurexin]. The affinity of the binding depends on the splicing of the insert SS4 of both neurexins. This binding plays a critical role in the formation of excitatory synapses as it briges the synaptic cleft. Without Neurexin1, LRRTM2 can't act on presynaptic differentiation leading to a reduction in the amount of excitatory synapses. In addition, the presynaptic receptors Neurexin 1 α and β are known to be receptors for <scene name='82/829346/Neurologin-neurexin/1'>Neurologin 1</scene> [http://proteopedia.org/wiki/index.php/3vkf], a protein similar to LRRTM2. Neurologin 1 also regulates the formation of excitatory synapses. | |
| - | + | ||
| + | '''Interaction with intracellular proteins''' | ||
| + | |||
| + | It has been shown that the binding of LRRTM2 with PSD-95 [http://proteopedia.org/wiki/index.php/1tq3] on the C-term fixation site was responsible for the regulation of <scene name='82/829346/Ampa/1'>AMPA receptor</scene> [http://proteopedia.org/wiki/index.php/AMPA] expression. The AMPA receptors ( AMPARs) are transmembrane receptors located on the postsynaptic membrane that interact with glutamates (neurotransmittters). So, the expression of LRRTM2 in the neurons of the hippocampus have a direct link with the density of excitatory synapses. The greater the quantity of LRRTM2, the greater the density of excitatory synapses. Thus, LRRTM2 has a direct influence on the glutamatergic synaptic transmission strength. | ||
| + | It has also been noted that the repression of LRRTM2 induced a decrease in the density of PSD-95. Thus, LRRTM2 recruits PSD-95 at postsynaptic density and then binds to PSD-95 via the ECFV cytoplasmic motif. The interaction of PSD-95 with glutamate receptors, located at the postsynaptic membrane, as well as with other synaptic synaptic proteins. | ||
| + | By the interaction with important postsynaptic components, LRRTM2 turns out to be crucial in the regulation of the postsynaptic fonctions and plasticity. | ||
| + | |||
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| + | [[Image:LRRTM2functions.png|1100px|left]] | ||
| + | |||
| + | == Related Structures == | ||
'''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 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. | |
'''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. | ||
| + | |||
| + | 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) | ||
| - | 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, Neuroligin1 binds to Neurexins 1, 2, and 3 ︎ but not ︎to variants, has a higher affinity with Neurexin 1 (-S4) than with Neurexin 1 (+S4) | ||
| - | + | 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. | ||
| Line 70: | Line 88: | ||
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 | ||
Current revision
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[1]to bridge the synaptic cleft.
Contents |
Structural highlights
| |||||||||||
Function
LRRTM2 protein play a key role in the regulation of the synaptic fonctions and development by interracting with various proteins both inside and outside the neuron cell.
Interaction with extracellular proteins
On the N-term fixation site, LRRTM2 binds specifically to Neurexin1 and [2]. The affinity of the binding depends on the splicing of the insert SS4 of both neurexins. This binding plays a critical role in the formation of excitatory synapses as it briges the synaptic cleft. Without Neurexin1, LRRTM2 can't act on presynaptic differentiation leading to a reduction in the amount of excitatory synapses. In addition, the presynaptic receptors Neurexin 1 α and β are known to be receptors for [3], a protein similar to LRRTM2. Neurologin 1 also regulates the formation of excitatory synapses.
Interaction with intracellular proteins
It has been shown that the binding of LRRTM2 with PSD-95 [4] on the C-term fixation site was responsible for the regulation of [5] expression. The AMPA receptors ( AMPARs) are transmembrane receptors located on the postsynaptic membrane that interact with glutamates (neurotransmittters). So, the expression of LRRTM2 in the neurons of the hippocampus have a direct link with the density of excitatory synapses. The greater the quantity of LRRTM2, the greater the density of excitatory synapses. Thus, LRRTM2 has a direct influence on the glutamatergic synaptic transmission strength. It has also been noted that the repression of LRRTM2 induced a decrease in the density of PSD-95. Thus, LRRTM2 recruits PSD-95 at postsynaptic density and then binds to PSD-95 via the ECFV cytoplasmic motif. The interaction of PSD-95 with glutamate receptors, located at the postsynaptic membrane, as well as with other synaptic synaptic proteins. By the interaction with important postsynaptic components, LRRTM2 turns out to be crucial in the regulation of the postsynaptic fonctions and plasticity.
Related Structures
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 neurexins[6]. This is due to the fact that some critical residues for binding with have been replaced in LRRTM3 and LRRTM4, such as , , and . 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
Neurexins (Nrxns) [7]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. ︎ have six whereas ︎ 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 [8]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 [9] 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
Neuroligins (NLs)[10] 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, 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
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160412/ https://pdf.sciencedirectassets.com/271175/1-s2.0-S0168010217X00047/1-s2.0-S0168010216302176/main.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEIn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJIMEYCIQD9y3Gq4IpA3WUL5u%2Fkg2WA1Xkc%2FecGOKwBvrh87jA43QIhALaUG9EO6UsgdfDX4BdAFQdHgdcRASV4GY5gcp4MpAU1KrQDCBEQAhoMMDU5MDAzNTQ2ODY1IgxX8k4XAFbLEwxUIxEqkQMGYQSzdSg4KJygQuQhcirZ5z1dcUiJllkhebembjnSpLm2HgwQyXo8kS7OyOG4LrZK%2FpuVLgcwKJPzhlzfC8hvL4XkbdOHINPOAHjqrQAZfDUTyerG37EygqlyBH3ozWLj6bBRzb4qjtTKHiJXIVViFUwE4kLnUx%2BG1P9nlMZKiKwjTTZANO6qdo02b0eBH5wtGZXkTThixMrkac5AkC%2F6lv55c6GQkaGJ7QFUTzuMDhw1jnjgjh3SYEvL3zSXYMMmK9cdAvX47pXUxrx2upPm%2B1b6tXK9t%2BtcMhmGekMeq%2BQ4vgAGco9W47wKMZckdEtWsBwLD0ouczegSiUsY2j7%2Bkbrq3doyu8IVfj2trxYgsDhsot0o9LFT6vU4OcBDau43lRiWt28NL9taG2HVIr6S0JpdQrG5GnhP%2B9JBw0NzpNienHWZklAjtH5Yf2UdelMJoVxQVhA5Wt%2BxJdRYEa96OmlsXN%2FPrTFepkkdCM8oRnTDPYIsrzdNE7ztyE%2BKdycj4X5AmvBRpmLhlhj8JCajzDXhObwBTrqAbLxyZNQ%2F%2BztbwIwb1i%2FYTwtf4elBbvP75%2F%2BPavRxseS9SYjHMist7P2A3ic9sXaaRIVHQ%2BiNot7dRJXTHEmnQm%2Fpv7wJS%2BL3FrBNKhq2dtEs3wZwYiSkGRlQcFqq9B%2F6z%2FEpYEhZyY%2BXvVFlPy3UBFWSae%2B7sI6WH7Ioqesc5tp20wMy%2B86dD5OmNOpvKjmiRLEEzQU3yDhDHJbx3MEUlMTaugj2oDUpQwOhwwHGH5RWTUcyZQY2%2FZXTfvrmb4CbE9z%2BStJMmKQNGFFSfwmHo5tGI5vdQhOhljI0Jbg6Uarx7PMrUlHTCMy%2FA%3D%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20200111T090940Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYRBGSTTXK%2F20200111%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=f3a0fb03947cf2be7f5c0d563d999a97cbc798dfcf6a9362970a2b4f22429f84&hash=733b1d2a78272d2393866d8fc6492b461308206ea979170d41dd5fa61f0ff15f&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0168010216302176&tid=spdf-83ad8d7e-b6c3-48f3-ac67-86f9a916e1d5&sid=45412b395b1d0047476b49a0dd1ef07e3ef6gxrqb&type=client https://www.sciencedirect.com/science/article/pii/S2211124715015375 https://www.sciencedirect.com/science/article/abs/pii/S0959438810001364#! https://www.karger.com/Article/FullText/341252 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160412/ https://www.uniprot.org/uniprot/O43300 https://books.google.fr/books?id=hLS9BAAAQBAJ&pg=PA325&lpg=PA325&dq=LRRTM2+cytoplasmic+domain&source=bl&ots=5qlA_emVJs&sig=ACfU3U3tO8IN9lWW0rq3DDJbolvaJAo6Tw&hl=fr&sa=X&ved=2ahUKEwij9K_eofLmAhVCqxoKHZzPD8oQ6AEwAnoECAsQAQ#v=onepage&q=LRRTM2%20cytoplasmic%20domain&f=false - Cell Adhesion Molecules: Implications in Neurological Diseases publié par Vladimir Berezin, Peter S. Walmod https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887770/ https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.13159 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
