Dataset Information

High-affinity interactions and signal transduction between A? oligomers and TREM2.

ABSTRACT: Rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD-associated TREM2 variants to various forms of A? and APOE in multiple assays. TREM2 interacts directly with various forms of A?, with highest affinity interactions observed between TREM2 and soluble A?42 oligomers. High-affinity binding of TREM2 to A? oligomers is characterized by very slow dissociation. Pre-incubation with A? is shown to block the interaction of APOE In cellular assays, AD-associated variants of TREM2 reduced the amount of A?42 internalized, and in NFAT assay, the R47H and R62H variants decreased NFAT signaling activity in response to A?42. These studies demonstrate i) a high-affinity interaction between TREM2 and A? oligomers that can block interaction with another TREM2 ligand and ii) that AD-associated TREM2 variants bind A? with equivalent affinity but show loss of function in terms of signaling and A? internalization.

SUBMITTER: Lessard CB

PROVIDER: S-EPMC6220267 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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High-affinity interactions and signal transduction between Aβ oligomers and TREM2.

Lessard Christian B CB Malnik Samuel L SL Zhou Yingyue Y Ladd Thomas B TB Cruz Pedro E PE Ran Yong Y Mahan Thomas E TE Chakrabaty Paramita P Holtzman David M DM Ulrich Jason D JD Colonna Marco M Golde Todd E TE

EMBO molecular medicine 20181101 11

Rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD-associated TREM2 variants to various forms of Aβ and APOE in multiple assays. TREM2 interacts directly with various forms of Aβ, with highest affinity interactions observed between TREM2 and soluble Aβ42 oligomers. High-affinity binding of TREM2 to Aβ oligomers is cha ...[more]

PMID: 30341064

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Project description:UnlabelledTwo-component systems (TCS) comprise histidine kinases and their cognate response regulators and allow bacteria to sense and respond to a wide variety of signals. Histidine kinases (HKs) phosphorylate and dephosphorylate their cognate response regulators (RRs) in response to stimuli. In general, these reactions appear to be highly specific and require an appropriate association between the HK and RR proteins. The Myxococcus xanthus genome encodes one of the largest repertoires of signaling proteins in bacteria (685 open reading frames [ORFs]), including at least 127 HKs and at least 143 RRs. Of these, 27 are bona fide NtrC-family response regulators, 21 of which are encoded adjacent to their predicted cognate kinases. Using system-wide profiling methods, we determined that the HK-NtrC RR pairs display a kinetic preference during both phosphotransfer and phosphatase functions, thereby defining cognate signaling systems in M. xanthus. Isothermal titration calorimetry measurements indicated that cognate HK-RR pairs interact with dissociation constants (Kd) of approximately 1 µM, while noncognate pairs had no measurable binding. Lastly, a chimera generated between the histidine kinase, CrdS, and HK1190 revealed that residues conferring phosphotransfer and phosphatase specificity dictate binding affinity, thereby establishing discrete protein-protein interactions which prevent cross talk. The data indicate that binding affinity is a critical parameter governing system-wide signaling fidelity for bacterial signal transduction proteins.ImportanceUsing in vitro phosphotransfer and phosphatase profiling assays and isothermal titration calorimetry, we have taken a system-wide approach to demonstrate specificity for a family of two-component signaling proteins in Myxococcus xanthus. Our results demonstrate that previously identified specificity residues dictate binding affinity and that phosphatase specificity follows phosphotransfer specificity for cognate HK-RR pairs. The data indicate that preferential binding affinity is the basis for signaling fidelity in bacterial two-component systems.

Dataset Information

High-affinity interactions and signal transduction between A? oligomers and TREM2.

Publications

High-affinity interactions and signal transduction between Aβ oligomers and TREM2.

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