Lymphocyte-specific protein-tyrosine kinase (Lck) plays an essential role in T cell receptor (TCR) signaling and T cell development, but its activation mechanism is not fully understood. To explore the possibility that plasma membrane (PM) lipids control TCR signaling activities of Lck, we measured the membrane binding properties of its regulatory Src homology 2 (SH2) and Src homology 3 domains. The Lck SH2 domain binds anionic PM lipids with high affinity but with low specificity. Electrostatic potential calculation, NMR analysis, and mutational studies identified the lipid-binding site of the Lck SH2 domain that includes surface-exposed basic, aromatic, and hydrophobic residues but not the phospho-Tyr binding pocket. Mutation of lipid binding residues greatly reduced the interaction of Lck with the ζ chain in the activated TCR signaling complex and its overall TCR signaling activities. These results suggest that PM lipids, including phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate, modulate interaction of Lck with its binding partners in the TCR signaling complex and its TCR signaling activities in a spatiotemporally specific manner via its SH2 domain.

Background:The influenza hemagglutinin fusion peptide is responsible for fusion of viral and endosomal membranes upon infection. Results: Negatively induced curvature and fusion activity were significantly reduced by changing the shape of the fusion peptide. Conclusion: The hemagglutinin fusion peptide structure promotes negative membrane curvature. Significance: This work enables elucidates how a crucial component of influenza infection functions and can be targeted.

The influenza virus is a major health concern associated with an estimated 5000 to 30,000 deaths every year (Reed et al. 2015) and a significant economic impact with the development of treatments, vaccinations and research (Molinari et al. 2007). The entirety of the influenza genome is comprised of only eleven coding genes. An enormous degree of variation in non-conserved regions leads to significant challenges in the development of inclusive inhibitors for treatment. The fusion peptide domain of the influenza A hemagglutinin (HA) is a promising candidate for treatment since it is one of the most highly conserved sequences in the influenza genome (Heiny et al. 2007), and it is vital to the viral life cycle. Hemagglutinin is a class I viral fusion protein that catalyzes the membrane fusion process during cellular entry and infection. Impediment of the hemagglutinin's function, either through incomplete post-translational processing (Klenk et al. 1975; Lazarowitz and Choppin 1975) or through mutations (Cross et al. 2001), leads to non-infective virus particles. This review will investigate current research on the role of hemagglutinin in the virus life cycle, its structural biology and mechanism as well as the central role of the hemagglutinin fusion peptide (HAfp) to influenza membrane fusion and infection.

Isotropically tumbling discoidal bicelles are a useful biophysical tool for the study of lipids and proteins by NMR, dynamic light scattering, and small-angle X-ray scattering. Isotropically tumbling bicelles present a low-curvature central region, typically enriched with DMPC in the lamellar state, and a highly curved detergent rim, typically composed of DHPC. In this report, we study the impact of the partitioning and induced curvature of a few molecules of a foreign lipid on the bicelle size, structure, and curvature. Previous approaches for studying curvature have focused on macroscopic and bulk properties of membrane curvature. In the approach presented here, we show that the conical shape of the DOPE lipid and the inverted-conical shape of the DPC lipid induce measurable curvature changes in the bicelle size. Bicelles with an average of 1.8 molecules of DOPE have marked increases in the size of bicelles, consistent with negative membrane curvature in the central region of the bicelle. With bicelle curvature models, radii of curvature on the order of -100 Å and below are measured, with a greater degree of curvature observed in the more pliable Lα state above the phase-transition temperature of DMPC. Bicelles with an average of 1.8 molecules of DPC are reduced in size, consistent with positive membrane curvature in the rim, and at higher temperatures, DPC is distributed in the central region to form mixed-micelle structures. We use translational and rotational diffusion measurements by NMR, size-exclusion chromatography, and structural models to quantitate changes in bicelle size, curvature, and lipid dynamics.

Mycobacteria tuberculosis (Mtb) inflicts a quarter of the worldwide population. Most drugs for treating tuberculosis target cell growth and division. With rising drug resistance, it becomes ever more urgent to better understand Mtb cell division. This process begins with the formation of the Z-ring via polymerization of FtsZ and anchoring of the Z-ring to the inner membrane. Here we show that the transmembrane protein FtsQ is a membrane anchor of the Mtb Z-ring. More specifically, FtsQ uses an Arg/Ala-rich helix in its otherwise disordered N-terminal cytoplasmic region to bind with the GTPase domain of FtsZ. Binding of FtsQ to the GTPase domain of FtsZ also has enormous implications for drug binding and Z-ring formation including its curvature.