Biology subjects

Lietzke, E. E.

Publications and source records attributed to Lietzke, E. E..

4 recordsLinked to original sources

bioRxiv2026

Investigating the therapeutic potential of soluble TREM2 interactions with Transgelin-2 in Alzheimer's disease

Triggering receptor expressed on myeloid cells 2 (TREM2) is a regulator of microglial function in Alzheimer's disease (AD), and its soluble ectodomain (sTREM2) has emerged as a potential neuroprotective factor. Recent work shows that sTREM2 exerts protective effects through direct interaction with neuronal transgelin-2 (TG2) and modulates downstream tau pathology, yet the molecular basis of this interaction remains unknown. Here, we use all-atom molecular dynamics simulations to define the structural mechanisms of sTREM2-TG2 binding. We identify an electrostatically driven interface centered on the TG2 calponin homology domain. This surface is engaged by a binding motif on sTREM2 in which charged anchoring residues are flanked by hydrophobic contacts. We further show that the AD-risk TREM2R47H variant maintains a more open, solvent-exposed CDR2 loop that redistributes interfacial contacts while preserving overall binding affinity, offering a structural explanation for reports that R47H does not exacerbate tau pathology in tauopathy models. Leveraging these insights, we design optimized sTREM2-derived peptides that outperform a previously reported therapeutic peptide in binding persistence, energetics, and recapitulation of native TG2 contacts, supporting engagement at the epitope through which sTREM2 suppresses tau phosphorylation. Taken together, our results define a mechanistic framework for the sTREM2-TG2 axis in AD and establish a structure-guided strategy for developing peptide modulators of this interaction.

bioengineering↗

bioRxiv2025

Lipoprotein lipase requires a flexible lid and stable C-terminal, both maintained by ApoC-II peptide binding

Lipoprotein lipase (LPL) is the rate-limiting enzyme responsible for hydrolyzing triglycerides in circulating lipoproteins. Reduced LPL activity contributes to hypertriglyceridemia, a major cardiovascular risk factor. LPL activity is thought to depend on the conformation of the lid domain, the lipid pore, N- and C-terminal domains (NTD, CTD), and stabilization of these domains by endogenous activators such as apolipoprotein C-II (ApoC-II). Despite major clinical significance, the structure-function relationship of LPLs functional domains and cofactors remain incompletely understood. To address this, we performed the longest known (1-{micro}s) molecular dynamics simulations of LPL independently and in complex with an ApoC-II mimetic peptide (ApoC-II-P). For the first time, we show that LPLs flexible lid can adopt multiple orientations, transitioning between open and closed states that regulate lipid pore access and catalytic activity. We also observed flipping of [~]180{degrees} by the CTD, a unique characteristic that dictates LPL activity when not in a closed lid state. Furthermore, ApoC-II-P stabilizes LPL by bridging its NTD and CTD, while maintaining an optimal lid orientation. Biochemical and cellular assays corroborate these findings, demonstrating that ApoC-II-P enhances LPL hydrolysis and supports noncanonical LPL functions. Together, these insights reveal previously unrecognized mechanisms governing LPL regulation and activity dynamics.

molecular biology↗

bioRxiv2024

The flexible stalk domain of sTREM2 modulates its interactions with phospholipids in the brain

The microglial surface protein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a critical role in mediating brain homeostasis and inflammatory responses in Alzheimers disease (AD). The soluble form of TREM2 (sTREM2) exhibits neuroprotective effects in AD, though the underlying mechanisms remain elusive. Moreover, differences in ligand binding between TREM2 and sTREM2, which have major implications for their roles in AD pathology, remain unexplained. To address these knowledge gaps, we conducted the most computationally intensive molecular dynamics simulations to date of (s)TREM2, exploring their interactions with key damage- and lipoprotein-associated phospholipids and the impact of the AD-risk mutation R47H. Our results demonstrate that the flexible stalk domain of sTREM2 serves as the molecular basis for differential ligand binding between sTREM2 and TREM2, facilitated by its role in modulating the dynamics of the Ig-like domain and altering the accessibility of canonical ligand binding sites. We identified a novel ligand binding site on sTREM2, termed the Expanded Surface 2, which emerges due to competitive binding of the stalk with the Ig-like domain. Additionally, we observed that the stalk domain itself functions as a site for ligand binding, with increased binding frequency in the presence of R47H. This suggests that sTREM2s neuroprotective role in AD may, at least in part, arise from the stalk domains ability to rescue dysfunctional ligand binding caused by AD-risk mutations. Lastly, our findings indicate that R47H-induced dysfunction in TREM2 may result from both diminished ligand binding due to restricted complementarity-determining region 2 loop motions and an impaired ability to differentiate between ligands, proposing a novel mechanism for loss-of-function. In summary, these results provide valuable insights into the role of sTREM2 in AD pathology, laying the groundwork for the design of new therapeutic approaches targeting (s)TREM2 in AD.

bioengineering↗

bioRxiv2020

Characterization of a gene-trap knockout mouse model of Scn2a encoding voltage-gated sodium channel Nav1.2

Recent large-scale genomic studies have revealed SCN2A as one of the most frequently mutated gene in patients with neurodevelopmental disorders including autism spectrum disorder and intellectual disability. SCN2A encodes for voltage-gated sodium channel isoform 1.2 (Nav1.2), which is mainly expressed in the central nervous system and responsible for the propagation of neuronal action potentials. Homozygous knockout (null) of Scn2a is perinatal lethal, whereas heterozygous knockout of Scn2a results in mild behavior abnormalities. To achieve a more substantial, but not complete, reduction of Scn2a expression, we characterized a Scn2a deficient mouse model using a targeted gene trap knockout (gtKO) strategy to recapitulate loss-of-function SCN2A disorders. This model produces viable homozygous mice (Scn2agtKO/gtKO) that can survive to adulthood, with markedly low but detectable Nav1.2 expression. Although Scn2agtKO/gtKO adult mice possess normal olfactory, taste, hearing, and mechanical sensitivity, they have decreased thermal and cold tolerance. Innate behaviors are profoundly impaired including impaired nesting, marble burying, and mating. These mice also have increased food and water intake with subsequent increases in fecal excretion of more but smaller fecal boli. This novel Scn2a gene trap knockout mouse thus provides a unique model to study pathophysiology associated with Scn2a deficiency.

neuroscience↗