5UD7

Crystal Structure of Wild-Type Ig-like Domain

Summary for 5UD7

• Entry DOI: 10.2210/pdb5ud7/pdb
• Descriptor: Triggering receptor expressed on myeloid cells 2, 2-acetamido-2-deoxy-beta-D-glucopyranose, IODIDE ION, ... (5 entities in total)
• Functional Keywords: ig-like domain, receptor, lipid binding, immunoregulatory, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 116887.36

Authors

Sudom, A.,Min, X.,Wang, Z. (deposition date: 2016-12-23, release date: 2018-04-04, Last modification date: 2024-10-23)

Primary citation

Sudom, A.,Talreja, S.,Danao, J.,Bragg, E.,Kegel, R.,Min, X.,Richardson, J.,Zhang, Z.,Sharkov, N.,Marcora, E.,Thibault, S.,Bradley, J.,Wood, S.,Lim, A.C.,Chen, H.,Wang, S.,Foltz, I.N.,Sambashivan, S.,Wang, Z.
Molecular basis for the loss-of-function effects of the Alzheimer's disease-associated R47H variant of the immune receptor TREM2.
J. Biol. Chem., 293:12634-12646, 2018

PubMed Abstract: Triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor expressed on the surface of microglia, macrophages, dendritic cells, and osteoclasts. The R47H TREM2 variant is a significant risk factor for late-onset Alzheimer's disease (AD), and the molecular basis of R47H TREM2 loss of function is an emerging area of TREM2 biology. Here, we report three high-resolution structures of the extracellular ligand-binding domains (ECDs) of R47H TREM2, apo-WT, and phosphatidylserine (PS)-bound WT TREM2 at 1.8, 2.2, and 2.2 Å, respectively. The structures reveal that Arg plays a critical role in maintaining the structural features of the complementarity-determining region 2 (CDR2) loop and the putative positive ligand-interacting surface (PLIS), stabilizing conformations capable of ligand interaction. This is exemplified in the PS-bound structure, in which the CDR2 loop and PLIS drive critical interactions with PS via surfaces that are disrupted in the variant. Together with and characterization, our structural findings elucidate the molecular mechanism underlying loss of ligand binding, putative oligomerization, and functional activity of R47H TREM2. They also help unravel how decreased and stability of TREM2 contribute to loss of function in disease.

PubMed: 29794134
DOI: 10.1074/jbc.RA118.002352

Experimental method

X-RAY DIFFRACTION (2.20002253654 Å)