scholarly journals Microtubule Lattice Spacing Governs Cohesive Envelope Formation of Tau Family Proteins

2021 ◽  
Author(s):  
Valerie Siahaan ◽  
Ruensern Tan ◽  
Tereza Humhalova ◽  
Lenka Libusova ◽  
Samuel E Lacey ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Molecular Basis ◽  
Lattice Spacing ◽  
Family Members ◽  
Motor Protein ◽  
Spatial Regulation ◽  
Intrinsically Disordered ◽  
Protein Map

Tau is an intrinsically-disordered microtubule-associated protein (MAP) implicated in neurodegenerative disease. On microtubules, tau molecules segregate into two kinetically distinct phases, consisting of either independently diffusing molecules or interacting molecules that form cohesive envelopes around microtubules. Envelopes differentially regulate lattice accessibility for other MAPs, but the mechanism of envelope formation remains unclear. Here, we find that tau envelopes form cooperatively, locally altering the spacing of tubulin dimers within the microtubule lattice. Envelope formation compacted the underlying lattice, whereas lattice extension induced tau-envelope disassembly. Investigating other members of the tau-MAP family, we find MAP2 similarly forms envelopes governed by lattice-spacing, whereas MAP4 cannot. Envelopes differentially biased motor protein movement, suggesting that tau family members could spatially divide the microtubule surface into functionally distinct segments. We conclude that the interdependent allostery between lattice-spacing and cooperative envelope formation provides the molecular basis for spatial regulation of microtubule-based processes by tau and MAP2.

scholarly journals The molecular basis for high affinity of a universal ligand for human bombesin receptor (BnR) family members

2012 ◽  
Vol 84 (7) ◽  
pp. 936-948 ◽  
Author(s):  
Hirotsugu Uehara ◽  
Simon J. Hocart ◽  
Nieves González ◽  
Samuel A. Mantey ◽  
Tomoo Nakagawa ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Family Members ◽  
High Affinity ◽  
Bombesin Receptor

scholarly journals Synergism between a simple sugar and a small intrinsically disordered protein mitigate the lethal stresses of severe water loss

2017 ◽  
Author(s):  
Skylar X. Kim ◽  
Gamze Çamdere ◽  
Xuchen Hu ◽  
Douglas Koshland ◽  
Hugo Tapia
Keyword(s):  
Water Loss ◽  
Molecular Basis ◽  
Intrinsically Disordered Protein ◽  
Biological Functions ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Drought Tolerant ◽  
Simple Sugar

ABSTRACTAnhydrobiotes are rare microbes, plants and animals that tolerate severe water loss. Understanding the molecular basis for their desiccation tolerance may provide novel insights into stress biology and critical tools for engineering drought-tolerant crops. Using the anhydrobiote, budding yeast, we show that trehalose and Hsp12, a small intrinsically disordered protein (sIDP) of the hydrophilin family, synergize to mitigate completely the inviability caused by the lethal stresses of desiccation. We show that these two molecules help to stabilize the activity and prevent aggregation of model proteins both in vivo and in vitro. We also identify a novel role for Hsp12 as a membrane remodeler, a protective feature not shared by another yeast hydrophilin, suggesting that sIDPs have distinct biological functions.

A molecular mechanism for Wnt ligand-specific signaling

Science ◽  
2018 ◽  
Vol 361 (6403) ◽  
pp. eaat1178 ◽  
Author(s):  
Marie Eubelen ◽  
Naguissa Bostaille ◽  
Pauline Cabochette ◽  
Anne Gauquier ◽  
Patricia Tebabi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Wnt Signaling ◽  
Molecular Mechanism ◽  
Family Members ◽  
Brain Endothelial Cells ◽  
Functional Diversification ◽  
Structural Determinants ◽  
Linker Region ◽  
Intrinsically Disordered ◽  
Wnt Ligands

Wnt signaling is key to many developmental, physiological, and disease processes in which cells seem able to discriminate between multiple Wnt ligands. This selective Wnt recognition or “decoding” capacity has remained enigmatic because Wnt/Frizzled interactions are largely incompatible with monospecific recognition. Gpr124 and Reck enable brain endothelial cells to selectively respond to Wnt7. We show that Reck binds with low micromolar affinity to the intrinsically disordered linker region of Wnt7. Availability of Reck-bound Wnt7 for Frizzled signaling relies on the interaction between Gpr124 and Dishevelled. Through polymerization, Dishevelled recruits Gpr124 and the associated Reck-bound Wnt7 into dynamic Wnt/Frizzled/Lrp5/6 signalosomes, resulting in increased local concentrations of Wnt7 available for Frizzled signaling. This work provides mechanistic insights into the Wnt decoding capacities of vertebrate cells and unravels structural determinants of the functional diversification of Wnt family members.

scholarly journals Oligomerization Mechanisms of an H-NS Family Protein, Pmr, Encoded on the Plasmid pCAR1 Provide a Molecular Basis for Functions of H-NS Family Members

PLoS ONE ◽  
2014 ◽  
Vol 9 (8) ◽  
pp. e105656 ◽  
Author(s):  
Chiho Suzuki ◽  
Kohei Kawazuma ◽  
Shoichiro Horita ◽  
Tohru Terada ◽  
Masaru Tanokura ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Family Members ◽  
Family Protein

scholarly journals Prosurvival Bcl-2 family members reveal a distinct apoptotic identity between conventional and plasmacytoid dendritic cells

2015 ◽  
Vol 112 (13) ◽  
pp. 4044-4049 ◽  
Author(s):  
Emma M. Carrington ◽  
Jian-Guo Zhang ◽  
Robyn M. Sutherland ◽  
Ingela B. Vikstrom ◽  
Jamie L. Brady ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Cell Survival ◽  
Molecular Basis ◽  
Family Members ◽  
Specific Inhibitor ◽  
Immune Intervention ◽  
Molecular Control ◽  
Plasmacytoid Dcs

Dendritic cells (DCs) are heterogeneous, comprising subsets with functional specializations that play distinct roles in immunity as well as immunopathology. We investigated the molecular control of cell survival of two main DC subsets: plasmacytoid DCs (pDCs) and conventional DCs (cDCs) and their dependence on individual antiapoptotic BCL-2 family members. Compared with cDCs, pDCs had higher expression of BCL-2, lower A1, and similar levels of MCL-1 and BCL-XL. Transgenic overexpression of BCL-2 increased the pDC pool size in vivo with only minor impact on cDCs. With a view to immune intervention, we tested BCL-2 inhibitors and found that ABT-199 (the BCL-2 specific inhibitor) selectively killed pDCs but not cDCs. Conversely, genetic knockdown of A1 profoundly reduced the proportion of cDCs but not pDCs. We also found that conditional ablation of MCL-1 significantly reduced the size of both DC populations in mice and impeded DC-mediated immune responses. Thus, we revealed that the two DC types have different cell survival requirements. The molecular basis of survival of different DC subsets thus advocates the antagonism of selective BCL-2 family members for treating diseases pertaining to distinct DC subsets.

scholarly journals Athletes with Neurodegenerative Disease: A Phenomenological Exploration of Family Members’ Experiences

2021 ◽  
Author(s):  
Matthew Smith ◽  
Georgia Young ◽  
John Batten ◽  
Keith Parry ◽  
Rosie Collins ◽  
...  
Keyword(s):  
Qualitative Study ◽  
Neurodegenerative Disease ◽  
Coping Strategies ◽  
Lived Experiences ◽  
Family Members ◽  
Emotional Responses ◽  
Raising Awareness ◽  
And Coping ◽  
Depth Interviews ◽  
Phenomenological Exploration

This qualitative study involved in-depth interviews with 15 family members (mainly partners and children) of deceased athletes who experienced deterioration in their neurological health towards the end of their life. The purpose of this study was to examine the stressors these family members experienced with the ailed players, their emotional responses to their family member’s condition, as well as the coping strategies they used. Vertical and horizontal thematic analyses were conducted on the data, which revealed five distinct temporal stages, a range of emotional responses, as well as accompanying stressors and coping strategies at each temporal stage. The findings are presented as an ethnodrama, capturing the lived experiences of participants. This ethnodrama aims to resonate with those caring for family members who are experiencing deteriorating neurological health, while also raising awareness of the various emotional responses of the individuals in these situations, as well as inviting dialogue and reflection about these issues.

scholarly journals Doublesex Mediates the Development of Sex-Specific Pheromone Organs in Bicyclus Butterflies via Multiple Mechanisms

2020 ◽  
Vol 37 (6) ◽  
pp. 1694-1707 ◽  
Author(s):  
Anupama Prakash ◽  
Antónia Monteiro
Keyword(s):  
Protein Expression ◽  
Expression Pattern ◽  
Chemical Communication ◽  
Molecular Basis ◽  
Functional Integration ◽  
Protein Expression Pattern ◽  
Bicyclus Anynana ◽  
Spatial Regulation ◽  
Wing Discs ◽  
Male Specific

Abstract The Bicyclus lineage of satyrid butterflies exhibits male-specific traits, the scent organs, used for chemical communication during courtship. These organs consist of tightly packed brush-like scales (hair-pencils) that rub against scent patches to disperse pheromones, but the evolution and molecular basis of these organ’s male-limited development remains unknown. Here, we examine the evolution of the number and location of the scent patches and hair-pencils within 53 species of Bicyclus butterflies, and the involvement of the sex determinant gene doublesex (dsx) in scent organ development in Bicyclus anynana using CRISPR/Cas9. We show that scent patches and hair-pencils arose via multiple, independent gains, in a correlated manner. Further, an initially nonsex-specific Dsx protein expression pattern in developing wing discs becomes male-specific and spatially refined to areas that develop the scent patches. Functional perturbations of dsx show that this gene activates patch development in males whereas hair-pencils develop in both sexes without Dsx input. Dsx in females is, instead, required to repress hair-pencils whereas Dsx in males regulates minor aspects of its development. These findings suggest that the patches and hair-pencils evolve as correlated composite organs presumably due to their functional integration. Divergence in the function of dsx isoforms occurred across the sexes, where the male isoform promotes patch development in males and the female isoform represses hair-pencil development in females, both leading to the development of male-limited traits. Furthermore, evolution in number of patches in males is due to the evolution of spatial regulation of dsx.

scholarly journals Private rare deletions in SEC16A and MAMDC4 may represent novel pathogenic variants in familial axial spondyloarthritis

2015 ◽  
Vol 75 (4) ◽  
pp. 772-779 ◽  
Author(s):  
Darren D O'Rielly ◽  
Mohammed Uddin ◽  
Dianne Codner ◽  
Michael Hayley ◽  
Jiayi Zhou ◽  
...  
Keyword(s):  
Axial Spondyloarthritis ◽  
Association Studies ◽  
Family Members ◽  
Genome Wide Association Studies ◽  
Intrinsically Disordered ◽  
Pathogenic Variants ◽  
Genome Wide ◽  
Multigenerational Family ◽  
Variant Frequency ◽  
The Impact

ObjectiveAxial spondyloarthritis (AxSpA) represents a group of inflammatory axial diseases that share common clinical and histopathological manifestations. Ankylosing spondylitis (AS) is the best characterised subset of AxSpA, and its genetic basis has been extensively investigated. Given that genome-wide association studies account for only 25% of AS heritability, the objective of this study was to discover rare, highly penetrant genetic variants in AxSpA pathogenesis using a well-characterised, multigenerational family.MethodsHLA-B*27 genotyping and exome sequencing was performed on DNA collected from available family members. Variant frequency was assessed by mining publically available datasets and using fragment analysis of unrelated AxSpA cases and unaffected controls. Gene expression was performed by qPCR, and protein expression was assessed by western blot analysis and immunofluorescence microscopy using patient-derived B-cell lines. Circular dichroism spectroscopy was performed to assess the impact of discovered variants on secondary structure.ResultsThis is the first report identifying two rare private familial variants in a multigenerational AxSpA family, an in-frame SEC16A deletion and an out-of-frame MAMDC4 deletion. Evidence suggests the causative mechanism for SEC16A appears to be a conformational change induced by deletion of three highly conserved amino acids from the intrinsically disordered Sec16A N-terminus and RNA-mediated decay for MAMDC4.ConclusionsThe results suggest that it is the presence of rare syntenic SEC16A and MAMDC4 deletions that increases susceptibility to AxSpA in family members who carry the HLA-B*27 allele.

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