Biology subjects

Dahl, G.

Publications and source records attributed to Dahl, G..

3 recordsLinked to original sources

bioRxiv2025

Structural basis of ATP release and ion selectivity in Pannexin1 channels

This study investigated the structural basis of adenosine triphosphate (ATP) release and ion selectivity by Pannexin1 (Panx1). The microinjection of active SRC tyrosine kinase increased Panx1-mediated currents in Panx1-expressing oocytes. Furthermore, a mutation mimicking phosphorylation at Y308 turned Panx1 into a constitutively open ATP-releasing channel with broad ion permeability. Cryogenic electron microscopy showed that for most maps, the channel alternated between wide and narrow conformations. However, in the map of the phosphomimetic Y308E mutation, Panx1 remains in a wide ATP-releasing conformation. The pore-lining residues, W74 and R75, are flexible and create, in concert with the sequestered N-terminal helix, a path for ATP. The data point to phosphorylation as a reversible switch that activates ATP permeability by stabilizing Panx1 in the ATP-releasing conformation, which is crucial for developing modulators for diseases such as cancer and chronic pain.

biophysics↗

bioRxiv2024

Unveiling the Power of PROTAC Valency: Navigating Cell Type-Specific Hook Effects

Targeted protein degradation (TPD) using bivalent proteolysis-targeting chimeras (PROTAC) technology has shown potential in expanding the "druggable" proteome. In their publication in Nature Chemical Biology, Imaide et al.1 posited that augmenting PROTAC valency could potentially lead to the formation of long-lived ternary complexes between PROTAC, the protein of interest (POI), and E3 ligase, thereby constraining the formation of potent binary complexes, as evidenced by a pronounced hook effect. The authors introduced SIM1, a trivalent von Hippel-Lindau (VHL)-based PROTAC, which exhibited a superior degradation profile in comparison to its parent molecule MZ1, towards bromo and extra terminal (BET) proteins, with a predilection for BRD2. The authors attributed this heightened degradation capability of SIM1 over bivalent MZ1 as supportive evidence for their hypothesis. While we concur with the notion that increasing valency and avidity could enhance the efficacy of a PROTAC, the claim that trivalent PROTACs unequivocally eliminate the hook effect is not entirely accurate. We propose that the presence or absence of a hook effect is influenced by numerous factors beyond PROTAC valency.

cancer biology↗

bioRxiv2024

A metastasis-associated Pannexin1 mutant (Panx11-89) forms a minimalist ATP release channel

A truncated form of the ATP release channel pannexin 1 (Panx1), Panx11-89, is enriched in metastatic breast cancer cells and has been proposed to mediate metastatic cell survival by increasing ATP release through mechanosensitive Panx1 channels. However, whether Panx11-89 on its own (without the presence of wtPanx1) mediates ATP release has not been tested. Here, we show that Panx11-89 by itself can form a constitutively active membrane channel, capable of releasing ATP even in the absence of wild type Panx1. Our biophysical characterization reveals that most basic structure-function features of the channel pore are conserved in the truncated Panx11-89 peptide. Thus, augmenting extracellular potassium ion concentrations enhances Panx11-89-mediated conductance. Moreover, despite the severe truncation, Panx11-89 retains the sensitivity to most of wtPanx1 channel inhibitors and can thus be targeted. Therefore, Panx1 blockers have the potential to be of therapeutic value to combat metastatic cell survival. Our study not only elucidates a mechanism for ATP release from cancer cells, but it also supports that the Panx11-89 mutant should facilitate structure-function analysis of Panx1 channels.

biophysics↗