NMR Studies of the C-Terminus of alpha4 Reveal Possible Mechanism of Its Interaction with MID1 and Protein Phosphatase 2A

Alpha4 is a regulatory subunit of the protein phosphatase family of enzymes and plays an essential role in regulating the catalytic subunit of PP2A (PP2Ac) within the rapamycin-sensitive signaling pathway. Alpha4 also interacts with MID1, a microtubule-associated ubiquitin E3 ligase that appears to regulate the function of PP2A. The C-terminal region of alpha4 plays a key role in the binding interaction of PP2Ac and MID1. Here we report on the solution structure of a 45-amino acid region derived from the C-terminus of alpha4 (alpha45) that binds tightly to MID1. In aqueous solution, alpha45 has properties of an intrinsically unstructured peptide although chemical shift index and dihedral angle estimation based on chemical shifts of backbone atoms indicate the presence of a transient α-helix. Alpha45 adopts a helix-turn-helix HEAT-like structure in 1% SDS micelles, which may mimic a negatively charged surface for which alpha45 could bind. Alpha45 binds tightly to the Bbox1 domain of MID1 in aqueous solution and adopts a structure consistent with the helix-turn-helix structure observed in 1% SDS. The structure of alpha45 reveals two distinct surfaces, one that can interact with a negatively charged surface, which is present on PP2A, and one that interacts with the Bbox1 domain of MID1

The gluten-free diet and its current application in coeliac disease and dermatitis herpetiformis

A gluten-free diet (GFD) is currently the only available therapy for coeliac disease (CD)

Element-Specific Orbital Character in a Nearly-Free-Electron Superconductor Ag5Pb2O6 Revealed by Core-Level Photoemission

Ag5Pb2O6 has attracted attentions due to its novel nearly-free-electron superconductivity, but its electronic structure and orbital character of the Cooper-pair electrons remain controversial. Here, we present a method utilizing core-level photoemission to show that Pb 6s electrons dominate near the Fermi level. We observe a strongly asymmetric Pb 4 f7/2 core-level spectrum, while a Ag 3d5/2 spectrum is well explained by two symmetric peaks. The asymmetry in the Pb 4 f7/2 spectrum originates from the local attractive interaction between conducting Pb 6s electrons and a Pb 4 f7/2 core hole, which implies a dominant Pb 6s contribution to the metallic conduction. In addition, the observed Pb 4 f7/2 spectrum is not explained by the well-known Doniach-Šunjić lineshape for a simple metal. The spectrum is successfully generated by employing a Pb 6s partial density of states from local density approximation calculations, thus confirming the Pb 6s dominant character and free-electron-like density of states of Ag5Pb2O6. © The Author(s) 2017

Molecular Dynamics Simulations of Model Trans-Membrane Peptides in Lipid Bilayers: A Systematic Investigation of Hydrophobic Mismatch

Hydrophobic mismatch, which is the difference between the hydrophobic length of trans-membrane segments of a protein and the hydrophobic width of the surrounding lipid bilayer, is known to play a role in membrane protein function. We have performed molecular dynamics simulations of trans-membrane KALP peptides (sequence: GKK(LA)(n)LKKA) in phospholipid bilayers to investigate hydrophobic mismatch alleviation mechanisms. By varying systematically the length of the peptide (KALP(15), KALP(19), KALP(23), KALP(27), and KALP(31)) and the lipid hydrophobic length (DLPC, DMPC, and DPPC), a wide range of mismatch conditions were studied. Simulations of durations of 50–200 ns show that under positive mismatch, the system alleviates the mismatch predominantly by tilting the peptide and to a smaller extent by increased lipid ordering in the immediate vicinity of the peptide. Under negative mismatch, alleviation takes place by a combination of local bilayer bending and the snorkeling of the lysine residues of the peptide. Simulations performed at a higher peptide/lipid molar ratio (1:25) reveal slower dynamics of both the peptide and lipid relative to those at a lower peptide/lipid ratio (1:128). The lysine residues have favorable interactions with specific oxygen atoms of the phospholipid headgroups, indicating the preferred localization of these residues at the lipid/water interface