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From Proteopedia
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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 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 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 Asp144 and Asp212 of LRRTMT2. It was also observed that LRRTM2 Glu348 interacts with Ca2+ through a water molecule. In top of the Ca2+ mediated interaction, there is the formation of a hydrogen bound between the Asp352 of LRRTM2 and the Arg206 of Nrxns as well as hydrophobic interactions between the LRRTM2 Phe357 and Nrxns Leu208. | + | 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. | ||
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3) C-term fixation domain | 3) 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) |
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A large number of researches shows that LRRTM2 is related to bipolar disorder. | A large number of researches shows that LRRTM2 is related to bipolar disorder. | ||
| - | A deletion (240 kb) at 5q31 chromosomal region containing LRRTM2 and CTNNA1 has been shown to be related to intellectual disability and developmental delay | + | A deletion (240 kb) at 5q31 chromosomal region containing LRRTM2 and CTNNA1 has been shown to be related to intellectual disability and developmental delay. |
== Relevance == | == Relevance == | ||
Revision as of 18:32, 13 January 2020
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, 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
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Function
Disease
A large number of researches shows that LRRTM2 is related to bipolar disorder. A deletion (240 kb) at 5q31 chromosomal region containing LRRTM2 and CTNNA1 has been shown to be related to intellectual disability and developmental delay.
Relevance
Neurexins
Neurexins (Nrxns) is a presynaptic organizer family which interact with several postsynaptic organizers. There are three Neurexin genes in vertebrates, each corresponds to a different promoter. Neurexins are characterized by their laminin-neurexin-sex hormone (LNS) domains. ︎ α-neurexins have six whereas ︎β-neurexins 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.
LRRTMs Family
Although four members of the human LRRTM family are highly similar in their LRR domains with >55% sequence identity. LRRTM1 and LRRTM2 have been extensively studied in the context of the interaction with Nrxn, whereas LRRTM3 and LRRTM4 have not. This is due to that critical residues for binding to have been replaced Nrxn1β in LRRTM3 and LRRTM4, such as Glu348, Asp352, and Phe357 of LRRTM2. For LRRTM3, the replacement of Glu348 by Val in LRRTM3 is likely to cause the abolishment of the coordination with Ca2+ in Nrxn1β. It is possible that other specific residue(s) of LRRTM3/4 may block the coordination.
Ligands
The structure of the complex Nrxn1β–LRRTM2 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.
Other synaptic organisers
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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)
Cbln1–GluD2
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
