Transient receptor potential vanilloid 6 (TRPV6), a calcium-selective channel possessing six transmembrane domains (S1-S6) and intracellular N and C termini, plays crucial roles in calcium absorption in epithelia and bone and is involved in human diseases including vitamin-D deficiency, osteoporosis, and cancer. The TRPV6 function and regulation remain poorly understood. Here we show that the TRPV6 intramolecular S4-S5 linker to C-terminal TRP helix (L/C) and N-terminal pre-S1 helix to TRP helix (N/C) interactions, mediated by Arg470:Trp593 and Trp321:Ile597 bonding, respectively, are autoinhibitory and are required for maintaining TRPV6 at basal states. Disruption of either interaction by mutations or blocking peptides activates TRPV6. The N/C interaction depends on the L/C interaction but not reversely. Three cationic residues in S5 or C terminus are involved in binding PIP2 to suppress both interactions thereby activating TRPV6. This study reveals “PIP2 - intramolecular interactions” regulatory mechanism of TRPV6 activation-autoinhibition, which will help elucidating the corresponding mechanisms in other TRP channels.

TRPV6, a Ca-selective channel, is abundantly expressed in the placenta, intestine, kidney and bone marrow. TRPV6 is vital to Ca homeostasis and its defective expression or function is linked to transient neonatal hyperparathyroidism, Lowe syndrome/Dent disease, renal stone, osteoporosis and cancers. The fact that the molecular mechanism underlying the function and regulation of TRPV6 is still not well understood hampers, in particular, the understanding of how TRPV6 contributes to breast cancer development. By electrophysiology and Ca imaging in Xenopus oocytes and cancer cells, molecular biology and numerical simulation, here we reveal an intramolecular S5/S6 helix interaction in TRPV6 that is functionally autoinhibitory and is mediated by the R532:D620 bonding. Predicted pathogenic mutation R532Q within S5 disrupts the S5/S6 interaction leading to gain-of-function of the channel, which promotes breast cancer cell progression through strengthening of the TRPV6/PI3K interaction, activation of a PI3K/Akt/GSK-3β cascade, and up-regulation of epithelial-mesenchymal transition and anti-apoptosis.

The most important application of anticancer drugs in various forms (alkylating agents, hormones agents, and antimetabolites) is the treatment of malignant diseases. Topological indices are widely used in the field of chemical and medical sciences, especially in studying the chemical, biological, clinical, and therapeutic aspects of drugs. In this article, the temperature indices in anticancer drugs molecular graphs such as Carmustine, Convolutamine F, Raloxifene, Tambjamine K, and Pterocellin B were calculated and then analyzed based on physical and chemical properties. The analysis was performed by identifying the best regression models based on temperature indices for six physical and chemical features of anticancer drugs. The results indicated that temperature indices were essential topological indices that predict the properties of anticancer drugs, such as boiling point, flash point, enthalpy, molar refractivity, molar volume, and polarizability. It was also observed that the r value of the regression model was more than 0.6, and the p value was less than 0.05.

Recently identified proton-activated chloride channel (PAC) contains two transmembrane helices (S1–S2) and is involved in lysosome function, hypoxia adaption, stroke, and carcinogenesis. Although a PAC structure was recently resolved, its gating and activation mechanisms remained largely unknown. By the two-electrode voltage clamp electrophysiology in Xenopus oocytes, we found that the hydrophobicity of site 304 at fenestrations, but not that of neighbor sites, is important for maintaining PAC at a closed state at pH 7.5. When activated at acidic pH, PAC activity significantly increased with the hydrophilicity of site 307 within S2, but not with that of neighbor sites, suggesting that 307 acts as an activation gate. We identified six conserved protonatable residues critical for proton-induced activation, consistent with structural studies. Our study depicted a scheme in which proton binding induces conformational changes from the W304-controlled closed state at fenestrations to an activated state controlled by activation gate I307 in helix S2.

Lysosomes are subject to perturbations that can cause damage to their limiting membrane. Osmotic shifts, pore-forming toxins, and the growth of luminal polymers or pathogens all stand to increase lysosomal membrane tension and/or disrupt the bilayer. In some contexts, this leads to lysosomal rupture and cell death. Here, we describe a mechanism that enables lysosomes to sense and respond to acute increases in tension of their limiting membrane. We report that the lysosome-resident nonselective cation channel, TMEM63A, can drive the directional flux of monovalent cations, major osmoticants, out of the lumen when gated by mechanical tension on the organelle. This results in the ability for lysosomes to relieve hydrostatic pressure and, proportionally, membrane tension, affording lysosomes the time to acquire additional lipids. Lysosomes without this mechanism—either because TMEM63A is deleted or in the case when cells express disease-causing variants of TMEM63A—are an order of magnitude more sensitive to lysis upon increases to their membrane tension when compared with their WT counterparts. These findings suggest that lysosomes are capable of regulating hydrostatic pressure and volume in response to high tension.

This study explores the degree energy of fuzzy graphs to establish fundamental spectral bounds and characterize adjacency structures. We derive upper bounds on the sum of squared degree eigenvalues based on vertex degree distributions and formulate constraints using the characteristic polynomial of the maximum degree matrix. Furthermore, we demonstrate that the average degree energy of a connected fuzzy graph remains strictly positive. The proposed framework is applied to protein–protein interaction networks, identifying critical proteins and enhancing network resilience analysis.