Membrane and Protein Interactions of the Pleckstrin Homology Domain Superfamily.

The human genome encodes about 285 proteins that contain at least one annotated pleckstrin homology (PH) domain. As the first phosphoinositide binding module domain to be discovered, the PH domain recruits diverse protein architectures to cellular membranes. PH domains constitute one of the largest protein superfamilies, and have diverged to regulate many different signaling proteins and modules such as Dbl homology (DH) and Tec homology (TH) domains. The ligands of approximately 70 PH domains have been validated by binding assays and complexed structures, allowing meaningful extrapolation across the entire superfamily. Here the Membrane Optimal Docking Area (MODA) program is used at a genome-wide level to identify all membrane docking PH structures and map their lipid-binding determinants. In addition to the linear sequence motifs which are employed for phosphoinositide recognition, the three dimensional structural features that allow peripheral membrane domains to approach and insert into the bilayer are pinpointed and can be predicted ab initio. The analysis shows that conserved structural surfaces distinguish which PH domains associate with membrane from those that do not. Moreover, the results indicate that lipid-binding PH domains can be classified into different functional subgroups based on the type of membrane insertion elements they project towards the bilayer

Advancing membrane biology with poly(styrene-co-maleic acid)-based native nanodiscs

CITATION: Overduin, M. & Klumperman, B. 2019. Advancing membrane biology with poly(styrene-co-maleic acid)-based native nanodiscs. European Polymer Journal, 110:63-68, doi:10.1016/j.eurpolymj.2018.11.015.The original publication is available at https://www.sciencedirect.com/science/article/pii/S0014305718311364ENGLISH ABSTRACT: The elucidation of the structures and interactions of proteins and lipids in intact biological membranes remains largely uncharted territory. However, this information is crucial for understanding how organelles are assembled and how transmembrane machines transduce signals. The challenge of seeing how lipids and proteins engage each other in vivo remains difficult but is being aided by a group of amphipathic copolymers that spontaneously fragment native membranes into native nanodiscs. Poly(styrene-co-maleic acid) (SMA) copolymers have proven adept at converting membranes, cells and tissues directly into SMA lipid particles (SMALPs), allowing endogenous lipid: protein complexes to be prepared and analyzed. Unlike other amphipathic polymers such as amphipols, SMALP formation requires no conventional detergents, which typically strip lipid molecules from proteins and can destabilize multimers. A collaborative community of hundreds of investigators known as the SMALP network has emerged to develop and apply new technologies and identify new challenges and design potential solutions. In this contribution, we review recent practices and progress, focusing on novel SMA copolymers, modifications, alternatives and mechanisms. In addition, a brief overview will be provided, with reference to the further contributions to this special issue on the SMALP technology.https://www.sciencedirect.com/science/article/pii/S0014305718311364https://www.sciencedirect.com/science/article/pii/S0014305718311364Publisher's versio

The role of hydrophobic interactions in ankyrin–spectrin complex formation

AbstractSpectrin and ankyrin are the key components of the erythrocyte cytoskeleton. The recently published crystal structure of the spectrin–ankyrin complex has indicated that their binding involves complementary charge interactions as well as hydrophobic interactions. However, only the former is supported by biochemical evidence. We now show that nonpolar interactions are important for high affinity complex formation, excluding the possibility that the binding is exclusively mediated by association of distinctly charged surfaces. Along these lines we report that substitution of a single hydrophobic residue, F917S in ankyrin, disrupts the structure of the binding site and leads to complete loss of spectrin affinity. Finally, we present data showing that minimal ankyrin binding site in spectrin is formed by helix 14C together with the loop between helices 15 B/C

Secondary structure and 1H, 13C, 15N resonance assignments of the endosomal sorting protein sorting nexin 3

Sorting nexin 3 (SNX3) belongs to a sub-family of sorting nexins that primarily contain a single Phox homology domain capable of binding phosphoinositides and membranes. We report the complete (1)H, (13)C and (15)N resonance assignments of the full-length human SNX3 protein and identification of its secondary structure elements, revealing a canonical fold and unstructured termini

NUNATARYUK: Permafrost thaw and the changing Arctic coast. Science for socio-economic adaptation

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Mechanistic basis of desmosome-targeted diseases

Desmosomes are dynamic junctions between cells that maintain the structural integrity of skin and heart tissues by withstanding shear forces. Mutations in component genes cause life-threatening conditions including arrhythmogenic right ventricular cardiomyopathy, and desmosomal proteins are targeted by pathogenic autoantibodies in skin blistering diseases such as pemphigus. Here, we review a set of newly discovered pathogenic alterations and discuss the structural repercussions of debilitating mutations on desmosomal proteins. The architectures of native desmosomal assemblies have been visualized by cryo-electron microscopy and cryo-electron tomography, and the network of protein domain interactions is becoming apparent. Plakophilin and desmoplakin mutations have been discovered to alter binding interfaces, structures, and stabilities of folded domains that have been resolved by X-ray crystallography and NMR spectroscopy. The flexibility within desmoplakin has been revealed by small-angle X-ray scattering and fluorescence assays, explaining how mechanical stresses are accommodated. These studies have shown that the structural and functional consequences of desmosomal mutations can now begin to be understood at multiple levels of spatial and temporal resolution. This review discusses the recent structural insights and raises the possibility of using modeling for mechanism-based diagnosis of how deleterious mutations alter the integrity of solid tissues

Serpentine (Floating) Ice Channels and their Interaction with Riverbed Permafrost in the Lena River Delta, Russia

Arctic deltas and their river channels are characterized by three components of the cryosphere: snow, river ice, and permafrost, making them especially sensitive to ongoing climate change. Thinning river ice and rising river water temperatures may affect the thermal state of permafrost beneath the riverbed, with consequences for delta hydrology, erosion, and sediment transport. In this study, we use optical and radar remote sensing to map ice frozen to the riverbed (bedfast ice) vs. ice, resting on top of the unfrozen water layer (floating or so-called serpentine ice) within the Arctic’s largest delta, the Lena River Delta. The optical data is used to differentiate elevated floating ice from bedfast ice, which is flooded ice during the spring melt, while radar data is used to differentiate floating from bedfast ice during the winter months. We use numerical modeling and geophysical field surveys to investigate the temperature field and sediment properties beneath the riverbed. Our results show that the serpentine ice identified with both types of remote sensing spatially coincides with the location of thawed riverbed sediment observed with in situ geoelectrical measurements and as simulated with the thermal model. Besides insight into sub-river thermal properties, our study shows the potential of remote sensing for identifying river channels with active sub-ice flow during winter vs. channels, presumably disconnected for winter water flow. Furthermore, our results provide viable information for the summer navigation for shallow-draught vessels