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| | ==Structure of TREM2 transmembrane helix in DPC micelles== | | ==Structure of TREM2 transmembrane helix in DPC micelles== |
| - | <StructureSection load='6z0g' size='340' side='right'caption='[[6z0g]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='6z0g' size='340' side='right'caption='[[6z0g]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6z0g]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Z0G OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Z0G FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6z0g]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Z0G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Z0G FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TREM2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6z0g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z0g OCA], [https://pdbe.org/6z0g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6z0g RCSB], [https://www.ebi.ac.uk/pdbsum/6z0g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6z0g ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6z0g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z0g OCA], [http://pdbe.org/6z0g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6z0g RCSB], [http://www.ebi.ac.uk/pdbsum/6z0g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6z0g ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/TREM2_HUMAN TREM2_HUMAN]] Progressive non-fluent aphasia;Amyotrophic lateral sclerosis;Nasu-Hakola disease;Semantic dementia;Behavioral variant of frontotemporal dementia. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/TREM2_HUMAN TREM2_HUMAN] Progressive non-fluent aphasia;Amyotrophic lateral sclerosis;Nasu-Hakola disease;Semantic dementia;Behavioral variant of frontotemporal dementia. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TREM2_HUMAN TREM2_HUMAN]] May have a role in chronic inflammations and may stimulate production of constitutive rather than inflammatory chemokines and cytokines. Forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells.<ref>PMID:10799849</ref> | + | [https://www.uniprot.org/uniprot/TREM2_HUMAN TREM2_HUMAN] May have a role in chronic inflammations and may stimulate production of constitutive rather than inflammatory chemokines and cytokines. Forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells.<ref>PMID:10799849</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Brunner, B]] | + | [[Category: Brunner B]] |
| - | [[Category: Haass, C]] | + | [[Category: Haass C]] |
| - | [[Category: Hagn, F]] | + | [[Category: Hagn F]] |
| - | [[Category: Schlepkow, K]] | + | [[Category: Schlepkow K]] |
| - | [[Category: Steiner, A]] | + | [[Category: Steiner A]] |
| - | [[Category: Steiner, H]] | + | [[Category: Steiner H]] |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Neurodegeneration]]
| + | |
| - | [[Category: Proteolysis]]
| + | |
| Structural highlights
Disease
TREM2_HUMAN Progressive non-fluent aphasia;Amyotrophic lateral sclerosis;Nasu-Hakola disease;Semantic dementia;Behavioral variant of frontotemporal dementia. The disease is caused by mutations affecting the gene represented in this entry.
Function
TREM2_HUMAN May have a role in chronic inflammations and may stimulate production of constitutive rather than inflammatory chemokines and cytokines. Forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells.[1]
Publication Abstract from PubMed
Sequence variants of the microglial expressed TREM2 (triggering receptor expressed on myeloid cells 2) are a major risk factor for late onset Alzheimer's disease. TREM2 requires a stable interaction with DAP12 in the membrane to initiate signaling, which is terminated by TREM2 ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase. To understand the structural basis for the specificity of the intramembrane cleavage event, we determined the solution structure of the TREM2 transmembrane helix (TMH). Caused by the presence of a charged amino acid in the membrane region, the TREM2-TMH adopts a kinked structure with increased flexibility. Charge removal leads to TMH stabilization and reduced dynamics, similar to its structure in complex with DAP12. Strikingly, these dynamical features match with the site of the initial gamma-secretase cleavage event. These data suggest an unprecedented cleavage mechanism by gamma-secretase where flexible TMH regions act as key determinants of substrate cleavage specificity.
gamma-Secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics.,Steiner A, Schlepckow K, Brunner B, Steiner H, Haass C, Hagn F EMBO J. 2020 Aug 24:e104247. doi: 10.15252/embj.2019104247. PMID:32830336[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 2000 May 15;164(10):4991-5. PMID:10799849
- ↑ Steiner A, Schlepckow K, Brunner B, Steiner H, Haass C, Hagn F. gamma-Secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics. EMBO J. 2020 Aug 24:e104247. doi: 10.15252/embj.2019104247. PMID:32830336 doi:http://dx.doi.org/10.15252/embj.2019104247
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