5eli | pdb_00005eli
Triggering receptor expressed on myeloid cells 2
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 PubMedGenetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 A TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer's disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer's risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer's risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms.,Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ Elife. 2016 Dec 20;5. pii: e20391. doi: 10.7554/eLife.20391. PMID:27995897[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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