Neuroligin-Neurexin Interaction: Difference between revisions
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There are two <scene name='Neuroligin-Neurexin_Interaction/Neurexin_opening/1'>types of Neurexins</scene>, α and β. While α-NRXNs are much larger than β-NRXNs, both contain a single LNS (Laminin, NRXN, sex-hormone-binding globulin domains) domain. Extensive alternative splicing at five unique positions generates thousands of NRXN isoforms which likely specify a “code” of interactions at synapses that varies by location and activity of the neuron.<ref name="Sudhof"/> All NRXN isoforms have the same <scene name='Neuroligin-Neurexin_Interaction/Jelly_roll/1'>“jelly roll fold”</scene> comprised of 14 beta sheets. The alternative splicing only <scene name='Neuroligin-Neurexin_Interaction/Spliced/1'>impacts one end of the jelly roll</scene>, including sheets 1, 2, 13 & 14 and the lone alpha helix in the LNS domain.<ref>PMID:10520997</ref> | There are two <scene name='Neuroligin-Neurexin_Interaction/Neurexin_opening/1'>types of Neurexins</scene>, α and β. While α-NRXNs are much larger than β-NRXNs, both contain a single LNS (Laminin, NRXN, sex-hormone-binding globulin domains) domain. Extensive alternative splicing at five unique positions generates thousands of NRXN isoforms which likely specify a “code” of interactions at synapses that varies by location and activity of the neuron.<ref name="Sudhof"/> All NRXN isoforms have the same <scene name='Neuroligin-Neurexin_Interaction/Jelly_roll/1'>“jelly roll fold”</scene> comprised of 14 beta sheets. The alternative splicing only <scene name='Neuroligin-Neurexin_Interaction/Spliced/1'>impacts one end of the jelly roll</scene>, including sheets 1, 2, 13 & 14 and the lone alpha helix in the LNS domain.<ref>PMID:10520997</ref> | ||
The <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_dimer_opening/1'>extracellular residues of NLGNs</scene>, which bind to the LNS domains of both alpha and beta NRXNs with nanomolar affinity, are <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_opening/1'>composed of a single domain</scene> that is homologous with [[acetylcholinesterase]] (AChE).<ref name="Sudhof"/> Neuroligin-4 consists of a twisted <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_helices_and_sheets/3'>12 stranded beta sheet surrounded by 14 alpha helices</scene>. Three intramolecular <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_disulfide/1'>disulfide bridges</scene> between residues Cys110-Cys146, Cys306-Cys317, and Cys476-Cys510, stabilize the structure. Neuroligins readily <scene name='Neuroligin-Neurexin_Interaction/Dimer/1'>form a dimmer</scene> consisting of two neuroligin subunits. 100% of the dimer <scene name='Neuroligin-Neurexin_Interaction/Hydrophobic_interactions/1'>interactions are hydrophobic</scene> with the most unique feature being a <scene name='Neuroligin-Neurexin_Interaction/4_helix_bundle/2'>prominent four-helix bundle</scene>(<scene name='Neuroligin-Neurexin_Interaction/4_helix_bundle_hydro/1'>Alternate View</scene>).<ref name="Fabrichny"/> The <scene name='Neuroligin-Neurexin_Interaction/Central_pocket/2'>central pocket within Neuroligin</scene>, which in Acetylcholinesterase contains the active center and oxyanion hole, is catalytically inactive due to a substitution of Gly for Ser <scene name='Neuroligin-Neurexin_Interaction/Central_pocket_gly/1'>at position 254</scene>, which is typically part of AChE’s hydrolytic catalytic triad. The <scene name='Neuroligin-Neurexin_Interaction/Cys_loop/3'>so-called Cys-Loop</scene> (Residues Cys110-Cys146) forms one side of the rim of the central pocket and is a homolog of the lid found in [[Lipase|lipases]] of the α/β-hydrolase fold family. This Cys-Loop blocks the entry of substrate to the central pocket and provides stability to the NLGN structure.<ref name="Fabrichny"/> | The <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_dimer_opening/1'>extracellular residues of NLGNs</scene>, which bind to the LNS domains of both alpha and beta NRXNs with nanomolar affinity, are <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_opening/1'>composed of a single domain</scene> that is homologous with [[acetylcholinesterase]] (AChE).<ref name="Sudhof"/> Neuroligin-4 consists of a twisted <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_helices_and_sheets/3'>12 stranded beta sheet surrounded by 14 alpha helices</scene>. Three intramolecular <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_disulfide/1'>disulfide bridges</scene> between residues Cys110-Cys146, Cys306-Cys317, and Cys476-Cys510, stabilize the structure. Neuroligins readily <scene name='Neuroligin-Neurexin_Interaction/Dimer/1'>form a dimmer</scene> consisting of two neuroligin subunits. 100% of the dimer <scene name='Neuroligin-Neurexin_Interaction/Hydrophobic_interactions/1'>interactions are hydrophobic</scene> with the most unique feature being a <scene name='Neuroligin-Neurexin_Interaction/4_helix_bundle/2'>prominent four-helix bundle</scene> (<scene name='Neuroligin-Neurexin_Interaction/4_helix_bundle_hydro/1'>Alternate View</scene>).<ref name="Fabrichny"/> The <scene name='Neuroligin-Neurexin_Interaction/Central_pocket/2'>central pocket within Neuroligin</scene>, which in Acetylcholinesterase contains the active center and oxyanion hole, is catalytically inactive due to a substitution of Gly for Ser <scene name='Neuroligin-Neurexin_Interaction/Central_pocket_gly/1'>at position 254</scene>, which is typically part of AChE’s hydrolytic catalytic triad. The <scene name='Neuroligin-Neurexin_Interaction/Cys_loop/3'>so-called Cys-Loop</scene> (Residues Cys110-Cys146) forms one side of the rim of the central pocket and is a homolog of the lid found in [[Lipase|lipases]] of the α/β-hydrolase fold family. This Cys-Loop blocks the entry of substrate to the central pocket and provides stability to the NLGN structure.<ref name="Fabrichny"/> | ||
<scene name='Neuroligin-Neurexin_Interaction/Combo/3'>NRXN-beta-1 is bound</scene> through its <scene name='Neuroligin-Neurexin_Interaction/Combo_hyper/1'>hypervariable loop edge</scene> to the <scene name='Neuroligin-Neurexin_Interaction/Combo_electro/2'>electronegative surface</scene> of the NLGN-4 molecule, <scene name='Neuroligin-Neurexin_Interaction/Combo_total/1'>opposite the Cys-loop</scene>. The NRXN-NLGN interface is established by both indirect and direct interactions. Indirect interactions include **coordination of a divalent calcium cation** by residues Asp 137, Asn 238, Val 154 and Ile 236 of NRXN-Beta1 and residues Gln 359 and Gly 360 of NLGN-4. Direct interactions between NRXN and NLGN include extensive hydrogen bonding and Van der Waals contacts as well as salt bridges between residues NRXN-Arg 109 & NLGN-Glu 270 and NRXN-Arg232 & NLGN Asp 351. The vast majority of these interactions are conserved among all neuroligin types.<ref name="Fabrichny"/> | <scene name='Neuroligin-Neurexin_Interaction/Combo/3'>NRXN-beta-1 is bound</scene> through its <scene name='Neuroligin-Neurexin_Interaction/Combo_hyper/1'>hypervariable loop edge</scene> to the <scene name='Neuroligin-Neurexin_Interaction/Combo_electro/2'>electronegative surface</scene> of the NLGN-4 molecule, <scene name='Neuroligin-Neurexin_Interaction/Combo_total/1'>opposite the Cys-loop</scene>. The NRXN-NLGN interface is established by both indirect and direct interactions. Indirect interactions include **coordination of a divalent calcium cation** by residues Asp 137, Asn 238, Val 154 and Ile 236 of NRXN-Beta1 and residues Gln 359 and Gly 360 of NLGN-4. Direct interactions between NRXN and NLGN include extensive hydrogen bonding and Van der Waals contacts as well as salt bridges between residues NRXN-Arg 109 & NLGN-Glu 270 and NRXN-Arg232 & NLGN Asp 351. The vast majority of these interactions are conserved among all neuroligin types.<ref name="Fabrichny"/> | ||