NM23 proteins: innocent bystanders or local energy boosters for CFTR?

NM23 proteins NDPK-A and -B bind to the cystic fibrosis (CF) protein CFTR in different ways from kinases such as PKA, CK2 and AMPK or linkers to cell calcium such as calmodulin and annexins. NDPK-A (not -B) interacts with CFTR through reciprocal AMPK binding/control, whereas NDPK-B (not -A) binds directly to CFTR. NDPK-B can activate G proteins without ligand-receptor coupling, so perhaps NDPK-B's binding influences energy supply local to a nucleotide-binding site (NBD1) needed for CFTR to function. Curiously, CFTR (ABC-C7) is a member of the ATP-binding cassette (ABC) protein family that does not obey 'clan rules'; CFTR channels anions and is not a pump, regulates disparate processes, is itself regulated by multiple means and is so pleiotropic that it acts as a hub that orchestrates calcium signaling through its consorts such as calmodulin/annexins. Furthermore, its multiple partners make CFTR dance to different tunes in different cellular and subcellular locations as it recycles from the plasma membrane to endosomes. CFTR function in airway apical membranes is inhibited by smoking which has been dubbed 'acquired CF'. CFTR alone among family members possesses a trap for other proteins that it unfurls as a 'fish-net' and which bears consensus phosphorylation sites for many protein kinases, with PKA being the most canonical. Recently, the site of CFTR's commonest mutation has been proposed as a knock-in mutant that alters allosteric control of kinase CK2 by log orders of activity towards calmodulin and other substrates after CFTR fragmentation. This link from CK2 to calmodulin that binds the R region invokes molecular paths that control lumen formation, which is incomplete in the tracheas of some CF-affected babies. Thus, we are poised to understand the many roles of NDPK-A and -B in CFTR function and, especially lumen formation, which is defective in the gut and lungs of many CF babies

Stabilizing Effects of Phosphorus-Doped Silicon Nanoparticle Anodes in Lithium-Ion Batteries

Phosphorus-doped silicon has been reported to exhibit improved cycling stability and/or higher capacity retention than pure silicon as the anode in lithium-ion batteries. However, crystallite size and particle morphology are difficult to decouple from compositional tuning during chemical modification. In this work, we explore direct solid-state routes to phosphorus doping of silicon powders relevant to electrochemical applications. A wide range of compositions are assessed, from 0.05 to 3.0 at % P, as well as a wide range of silicon starting materials of varying crystallinity, particle size, and particle morphology. Successful incorporation of phosphorus into the silicon lattice is best confirmed by X-ray diffraction; the Si(111) reflection shifts to higher angles as consistent with the known lattice contraction of 0.002 Å per 1 at % phosphorus. The addition of phosphorus to Si nanoparticles (100–500 nm) in the high doping regime causes grain coarsening and catalyzes an increase in crystallinity. On the other hand, dilute doping of phosphorus can be carried out without great alteration of the nanoparticulate morphology. The opposite effect occurs for very large microparticles (>10 μm), whereby the doping is concomitant with a disruption of the crystal lattice and reduction of the crystallite size. These effects are borne out in both the electrochemical stability over long-term cycling in a lithium-ion half-cell as well as in the thermal stability under high-temperature decomposition. By comparison across a wide range of pure and P-doped materials of varying particle and crystallite sizes, the independent effects of doping and structure on thermal and electrochemical stability are able to be decoupled herein. A stabilizing effect is most significant when phosphorus doping is dilute and heterogeneous (surface-enriched) within the silicon nanoparticles

Processing and function of CFTR-ΔF508 are species-dependent

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis. The most common mutation, a deletion of the phenylalanine at position 508 (ΔF508), disrupts processing of the protein. Nearly all human CFTR-ΔF508 is retained in the endoplasmic reticulum and degraded, preventing maturation to the plasma membrane. In addition, the F508 deletion reduces the activity of single CFTR channels. Human CFTR-ΔF508 has been extensively studied to better understand its defects. Here, we adopted a cross-species comparative approach, examining human, pig, and mouse CFTR-ΔF508. As with human CFTR-ΔF508, the ΔF508 mutation reduced the single-channel activity of the pig and mouse channels. However, the mutant pig and mouse proteins were at least partially processed like their wild-type counterparts. Moreover, pig and mouse CFTR-ΔF508 partially restored transepithelial Cl− transport to CF airway epithelia. Our data, combined with earlier work, suggest that there is a gradient in the severity of the CFTR-ΔF508 processing defect, with human more severe than pig or mouse. These findings may explain some previously puzzling observations in CF mice, they have important implications for evaluation of potential therapeutics, and they suggest new strategies for discovering the mechanisms that disrupt processing of human CFTR-ΔF508