Structure of the human K13.1(THIK-1) channel reveals a novel hydrophilic pore restriction and lipid cofactor site.

The halothane-inhibited K leak potassium channel K13.1 (THIK-1) is found in diverse cells including neurons and microglia where it affects surveillance6, synaptic pruning7, phagocytosis7, and inflammasome-mediated interleukin-1β release. As with many Ks and other voltage-gated ion channel (VGIC) superfamily members, polyunsaturated fatty acid (PUFA) lipids modulate K13.

Membrane potential accelerates sugar uptake by stabilizing the outward facing conformation of the Na/glucose symporter vSGLT.

Sodium-dependent glucose transporters (SGLTs) couple a downhill Na ion gradient to actively transport sugars. Here, we investigate the impact of the membrane potential on vSGLT structure and function using sugar uptake assays, double electron-electron resonance (DEER), electrostatic calculations, and kinetic modeling. Negative membrane potentials, as present in all cell types, shift the conformational equilibrium of vSGLT towards an outward-facing conformation, leading to increased sugar transport rates.

Mechanism of substrate binding and transport in BASS transporters.

The bile acid sodium symporter (BASS) family transports a wide array of molecules across membranes, including bile acids in humans, and small metabolites in plants. These transporters, many of which are sodium-coupled, have been shown to use an elevator mechanism of transport, but exactly how substrate binding is coupled to sodium ion binding and transport is not clear. Here, we solve the crystal structure at 2.

Mechanism of substrate binding and transport in BASS transporters.

The Bile Acid Sodium Symporter (BASS) family transports a wide array of molecules across membranes, including bile acids in humans, and small metabolites in plants. These transporters, many of which are sodium-coupled, have been shown to use an elevator mechanism of transport, but exactly how substrate binding is coupled to sodium ion binding and transport is not clear. Here we solve the crystal structure at 2.

The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2.

Phosphatase and tensin homologue (PTEN) and SH2-containing inositol 5'-phosphatase 2 (SHIP2) are structurally and functionally similar. They both consist of a phosphatase (Ptase) domain and an adjacent C2 domain, and both proteins dephosphorylate phosphoinositol-tri(3,4,5)phosphate, PI(3,4,5)P; PTEN at the 3-phophate and SHIP2 at the 5-phosphate. Therefore, they play pivotal roles in the PI3K/Akt pathway.

General principles of secondary active transporter function.

Transport of ions and small molecules across the cell membrane against electrochemical gradients is catalyzed by integral membrane proteins that use a source of free energy to drive the energetically uphill flux of the transported substrate. Secondary active transporters couple the spontaneous influx of a "driving" ion such as Na or H to the flux of the substrate. The thermodynamics of such cyclical non-equilibrium systems are well understood, and recent work has focused on the molecular mechanism of secondary active transport.

Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes.

Association of peripheral proteins with lipid bilayers regulates membrane signaling and dynamics. Pleckstrin homology (PH) domains bind to phosphatidylinositol phosphate (PIP) molecules in membranes. The effects of local PIP enrichment on the interaction of PH domains with membranes is unclear.

Modes of Interaction of Pleckstrin Homology Domains with Membranes: Toward a Computational Biochemistry of Membrane Recognition.

Pleckstrin homology (PH) domains mediate protein-membrane interactions by binding to phosphatidylinositol phosphate (PIP) molecules. The structural and energetic basis of selective PH-PIP interactions is central to understanding many cellular processes, yet the molecular complexities of the PH-PIP interactions are largely unknown. Molecular dynamics simulations using a coarse-grained model enables estimation of free-energy landscapes for the interactions of 12 different PH domains with membranes containing PIP or PIP, allowing us to obtain a detailed molecular energetic understanding of the complexities of the interactions of the PH domains with PIP molecules in membranes.

Structure and lipid-binding properties of the kindlin-3 pleckstrin homology domain.

Kindlins co-activate integrins alongside talin. They possess, like talin, a FERM domain (4.1-erythrin-radixin-moiesin domain) comprising F0-F3 subdomains, but with a pleckstrin homology (PH) domain inserted in the F2 subdomain that enables membrane association.

Association of Peripheral Membrane Proteins with Membranes: Free Energy of Binding of GRP1 PH Domain with Phosphatidylinositol Phosphate-Containing Model Bilayers.

Understanding the energetics of peripheral protein-membrane interactions is important to many areas of biophysical chemistry and cell biology. Estimating free-energy landscapes by molecular dynamics (MD) simulation is challenging for such systems, especially when membrane recognition involves complex lipids, e.g.