
LRMP inhibits the cAMP-dependent potentiation of HCN4 channels by disrupting the intramolecular signal transduction between cyclic nucleotide binding and channel gating, in an HCN4-specific manner.


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Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation of HCN4 but the interaction domains, mechanisms of action, and basis for isoform-specificity remain unknown. Here we identify the domains of LRMP essential for regulation. We show that LRMP acts by disrupting the intramolecular signal transduction between cyclic nucleotide binding and gating. And we demonstrate that multiple unique regions in HCN4 are required for LRMP isoform-specificity. Using patch clamp electrophysiology and Förster resonance energy transfer (FRET), we showed that the initial 227 residues of LRMP and the N-terminus of HCN4 are necessary for LRMP to interact with HCN4. We found that the HCN4 N-terminus and HCN4-specific residues in the C-linker are necessary for regulation of HCN4 by LRMP. And we demonstrate that LRMP-regulation can be conferred to HCN2 by addition of the HCN4 N-terminus along with mutation of 5 residues in the S5 region and C-linker to the cognate HCN4 residues. Taken together, these results suggest that LRMP inhibits HCN4 through an isoform-specific interaction involving the N-terminals of both proteins that prevents the transduction of cAMP binding into a change in channel gating via an HCN4-specific orientation of the N-terminus, C-linker, and S4-S5 linker.

### Competing Interest Statement

The authors have declared no competing interest.

LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction

lrmp-disrupts-camp-dependent-regulation-of-hcn4-channels-by-interfering-with-intramolecular-signal-transduction


LRMP Disrupts cAMP-Dependent Regulation of HCN4 Channels by Interfering with Intramolecular Signal Transduction


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Structural insights into how chemically diverse bitter compounds activate the human bitter taste receptor TAS2R14.


Structures of the TAS2R14 taste receptor.

A bitter-taste receptor activated in a surprising way

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Cryo-Electron Microscopy Reveals Molecular Mechanisms of Bitter Taste Receptor Activation



Cholesterol acts as an orthosteric agonist, while the bitter tastant cmpd28.1 functions as a positive allosteric modulator with direct agonist activity at the bitter taste receptor TAS2R14.


Cryo-electron microscopy structures of the type 2 taste receptor TAS2R14 in complex with Ggust and Gi1 identify cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator and agonist.

Bitter taste receptor activation by cholesterol and an intracellular tastant - Nature

structural-insights-into-bitter-taste-receptor-tas2r14-activation-by-cholesterol-and-an-intracellular-bitter-tastant


Structural Insights into Bitter Taste Receptor TAS2R14 Activation by Cholesterol and an Intracellular Bitter Tastant



Gasdermin D is activated for pore formation and pyroptosis through reversible S-palmitoylation, which can occur on both the cleaved N-terminal domain and the intact full-length protein.


ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D - Nature

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Palmitoylation Activates Gasdermin D for Pyroptosis and Cytokine Secretion Downstream of Inflammasome Activation



The Integrator complex uses a multi-step mechanism involving major structural rearrangements to terminate RNA polymerase II transcription by opening the DSIF DNA clamp and preventing Pol II rebinding.


Cryo-electron microscopy structures of the human Integrator complex in three different functional states shed light on how Integrator terminates RNA polymerase II (Pol II) transcription by disengaging Pol II from the DNA template.

Structural basis of Integrator-dependent RNA polymerase II termination - Nature

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Structural Insights into Integrator-Mediated RNA Polymerase II Termination Mechanism



The C. elegans antiviral complex comprising Dicer (DCR-1), the RIG-I-like helicase DRH-1, and the dsRNA binding protein RDE-4 cooperate to cleave viral dsRNA in an ATP-dependent and terminus-specific manner, with DRH-1 playing a dominant role in ATP hydrolysis and processive cleavage.


Invertebrates use the endoribonuclease Dicer to cleave viral dsRNA during antiviral defense, while vertebrates use RIG-I-like Receptors (RLRs), which bind viral dsRNA to trigger an interferon response. While some invertebrate Dicers act alone during antiviral defense, C. elegans Dicer acts in a complex with a dsRNA binding protein called RDE-4, and an RLR ortholog called DRH-1. We used biochemical and structural techniques to provide mechanistic insight into how these proteins function together. We found RDE-4 is important for ATP-independent and ATP-dependent cleavage reactions, while helicase domains of both DCR-1 and DRH-1 contribute to ATP-dependent cleavage. DRH-1 plays the dominant role in ATP hydrolysis, and like mammalian RLRs, has an N-terminal domain that functions in autoinhibition. A cryo-EM structure indicates DRH-1 interacts with DCR-1’s helicase domain, suggesting this interaction relieves autoinhibition. Our study unravels the mechanistic basis of the collaboration between two helicases from typically distinct innate immune defense pathways.

### Competing Interest Statement

The authors have declared no competing interest.

C. elegans Dicer acts with the RIG-I-like helicase DRH-1 and RDE-4 to cleave dsRNA

mechanistic-insights-into-the-collaboration-of-dicer-rig-i-like-helicase-and-dsrna-binding-protein-in-antiviral-defense-in-c-elegans


Mechanistic Insights into the Collaboration of Dicer, RIG-I-like Helicase, and dsRNA Binding Protein in Antiviral Defense in C. elegans
