scholarly journals Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies

2020 ◽  
Vol 29 (7) ◽  
pp. 1107-1120 ◽  
Author(s):  
Xabier Elorza-Vidal ◽  
Efren Xicoy-Espaulella ◽  
Adrià Pla-Casillanis ◽  
Marta Alonso-Gardón ◽  
Héctor Gaitán-Peñas ◽  
...  
Keyword(s):  
Structural Model ◽  
Clinical Phenotype ◽  
Structural Basis ◽  
Recessive Character ◽  
Adhesion Protein ◽  
Recessive Mutations ◽  
Cross Links ◽  
Interacting Surfaces ◽  
Ig Domain ◽  
Subcortical Cysts

Abstract Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a type of leukodystrophy characterized by white matter edema, and it is caused mainly by recessive mutations in MLC1 and GLIALCAM genes. These variants are called MLC1 and MLC2A with both types of patients sharing the same clinical phenotype. In addition, dominant mutations in GLIALCAM have also been identified in a subtype of MLC patients with a remitting phenotype. This variant has been named MLC2B. GLIALCAM encodes for an adhesion protein containing two immunoglobulin (Ig) domains and it is needed for MLC1 targeting to astrocyte–astrocyte junctions. Most mutations identified in GLIALCAM abolish GlialCAM targeting to junctions. However, it is unclear why some mutations behave as recessive or dominant. Here, we used a combination of biochemistry methods with a new developed anti-GlialCAM nanobody, double-mutants and cysteine cross-links experiments, together with computer docking, to create a structural model of GlialCAM homo-interactions. Using this model, we suggest that dominant mutations affect different GlialCAM–GlialCAM interacting surfaces in the first Ig domain, which can occur between GlialCAM molecules present in the same cell (cis) or present in neighbouring cells (trans). Our results provide a framework that can be used to understand the molecular basis of pathogenesis of all identified GLIALCAM mutations.

scholarly journals Structural Basis for the C-Terminal Domain of Mycobacterium tuberculosis Ribosome Maturation Factor RimM to Bind Ribosomal Protein S19

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 597
Author(s):  
Haoran Zhang ◽  
Qiuxiang Zhou ◽  
Chenyun Guo ◽  
Liubin Feng ◽  
Huilin Wang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Ribosomal Protein ◽  
Solution Structure ◽  
Molecular Mechanisms ◽  
Structural Model ◽  
Ribosomal Subunit ◽  
Structural Basis ◽  
Hydrophobic Core ◽  
Terminal Domain ◽  
Ribosomal Protein S19

Multidrug-resistant tuberculosis (TB) is a serious threat to public health, calling for the development of new anti-TB drugs. Chaperon protein RimM, involved in the assembly of ribosomal protein S19 into 30S ribosomal subunit during ribosome maturation, is a potential drug target for TB treatment. The C-terminal domain (CTD) of RimM is primarily responsible for binding S19. However, both the CTD structure of RimM from Mycobacterium tuberculosis (MtbRimMCTD) and the molecular mechanisms underlying MtbRimMCTD binding S19 remain elusive. Here, we report the solution structure, dynamics features of MtbRimMCTD, and its interaction with S19. MtbRimMCTD has a rigid hydrophobic core comprised of a relatively conservative six-strand β-barrel, tailed with a short α-helix and interspersed with flexible loops. Using several biophysical techniques including surface plasmon resonance (SPR) affinity assays, nuclear magnetic resonance (NMR) assays, and molecular docking, we established a structural model of the MtbRimMCTD–S19 complex and indicated that the β4-β5 loop and two nonconserved key residues (D105 and H129) significantly contributed to the unique pattern of MtbRimMCTD binding S19, which might be implicated in a form of orthogonality for species-dependent RimM–S19 interaction. Our study provides the structural basis for MtbRimMCTD binding S19 and is beneficial to the further exploration of MtbRimM as a potential target for the development of new anti-TB drugs.

scholarly journals Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain

2019 ◽  
Author(s):  
Theresia Gutmann ◽  
Ingmar Schäfer ◽  
Chetan Poojari ◽  
Beate Brankatschk ◽  
Ilpo Vattulainen ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Binding Sites ◽  
Structural Model ◽  
Receptor Site ◽  
Insulin Binding ◽  
Proximal Region ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Structure Based Drug Design ◽  
Receptor Interactions

AbstractGlucose homeostasis and growth essentially depend on the peptide hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand–receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have only resolved site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we determined the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin–site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis enabling a comprehensive description of ligand–receptor interactions that ultimately will inform new approaches to structure-based drug design.In briefA cryo-EM structure of the complete insulin receptor ectodomain saturated with four insulin ligands is reported. The structural model of the insulin–insulin receptor complex adopts a T-shaped conformation, reveals two additional insulin-binding sites potentially involved in the initial interaction of insulin with its receptor, and resolves the membrane proximal region.

scholarly journals Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2684 ◽  
Author(s):  
Giacomo Milletti ◽  
Luisa Strocchio ◽  
Daria Pagliara ◽  
Katia Girardi ◽  
Roberto Carta ◽  
...  
Keyword(s):  
Dna Repair ◽  
Fanconi Anemia ◽  
Clinical Phenotype ◽  
Bone Marrow Failure ◽  
Therapeutic Approaches ◽  
Dna Repair Mechanisms ◽  
Solid Malignancies ◽  
Interstrand Cross Links ◽  
Repair Mechanisms ◽  
Cross Links

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), and a predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved in the FA pathway are associated with the development of sporadic hematological and solid malignancies. The key function of the FA pathway is to orchestrate proteins involved in the repair of interstrand cross-links (ICLs), to prevent genomic instability and replication stress. Recently, many studies have highlighted the importance of FA genes in noncanonical pathways, such as mitochondria homeostasis, inflammation, and virophagy, which act, in some cases, independently of DNA repair processes. Thus, primary defects in DNA repair mechanisms of FA patients are typically exacerbated by an impairment of other cytoprotective pathways that contribute to the multifaceted clinical phenotype of this disease. In this review, we summarize recent advances in the understanding of the pathogenesis of FA, with a focus on the cytosolic noncanonical roles of FA genes, discussing how they may contribute to cancer development, thus suggesting opportunities to envisage novel therapeutic approaches.

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

2016 ◽  
Vol 44 (2) ◽  
pp. 595-600 ◽  
Author(s):  
Verònica Casadó-Anguera ◽  
Jordi Bonaventura ◽  
Estefanía Moreno ◽  
Gemma Navarro ◽  
Antoni Cortés ◽  
...  
Keyword(s):  
Structural Model ◽  
Dopamine D2 Receptor ◽  
Ex Vivo ◽  
D2 Receptor ◽  
Drug Dosage ◽  
D1 Receptor ◽  
Structural Basis ◽  
Dopamine D2 ◽  
Allosteric Mechanisms ◽  
Adenosine A2a

Heteromers of G-protein-coupled receptors (GPCRs) have emerged as potential novel targets for drug development. Accumulating evidence indicates that GPCRs can form homodimers and heteromers, with homodimers being the predominant species and oligomeric receptors being formed as multiples of dimers. Recently, heterotetrameric structures have been proposed for dopamine D1 receptor (D1R)–dopamine D3 receptor (D3R) and adenosine A2A receptor (A2AR)–dopamine D2 receptor (D2R) heteromers. The structural model proposed for these complexes is a heteromer constituted by two receptor homodimers. The existence of GPCR homodimers and heteromers provides a structural basis for inter-protomer allosteric mechanisms that might account for a multiplicity of unique pharmacological properties. In this review, we focus on the A2AR–D2R heterotetramer as an example of an oligomeric structure that is key in the modulation of striatal neuronal function. We also review the interfaces involved in this and other recently reported heteromers of GPCRs. Furthermore, we discuss several published studies showing the ex vivo expression of A2AR–D2R heteromers. The ability of A2AR agonists to decrease the affinity of D2R agonists has been reported and, on the basis of this interaction, A2AR antagonists have been proposed as potential drugs for the treatment of Parkinson's disease. The heterotetrameric structure of the A2AR–D2R complex offers a novel model that can provide new clues about how to adjust the drug dosage to the expected levels of endogenous adenosine.

scholarly journals Structural basis for virulence regulation in Vibrio cholerae by unsaturated fatty acid components of bile

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Justin T. Cruite ◽  
Gabriela Kovacikova ◽  
Kenzie A. Clark ◽  
Anne K. Woodbrey ◽  
Karen Skorupski ◽  
...  
Keyword(s):  
Vibrio Cholerae ◽  
Structural Model ◽  
Unsaturated Fatty Acids ◽  
Diarrheal Disease ◽  
Bacterial Pathogen ◽  
Virulence Gene ◽  
Structural Basis ◽  
Active Conformation ◽  
Structural Mechanism ◽  
Virulence Gene Regulation

AbstractThe AraC/XylS-family transcriptional regulator ToxT is the master virulence activator of Vibrio cholerae, the gram-negative bacterial pathogen that causes the diarrheal disease cholera. Unsaturated fatty acids (UFAs) found in bile inhibit the activity of ToxT. Crystal structures of inhibited ToxT bound to UFA or synthetic inhibitors have been reported, but no structure of ToxT in an active conformation had been determined. Here we present the 2.5 Å structure of ToxT without an inhibitor. The structure suggests release of UFA or inhibitor leads to an increase in flexibility, allowing ToxT to adopt an active conformation that is able to dimerize and bind DNA. Small-angle X-ray scattering was used to validate a structural model of an open ToxT dimer bound to the cholera toxin promoter. The results presented here provide a detailed structural mechanism for virulence gene regulation in V. cholerae by the UFA components of bile and other synthetic ToxT inhibitors.

Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab

Science ◽  
2020 ◽  
Vol 367 (6483) ◽  
pp. 1224-1230 ◽  
Author(s):  
Lionel Rougé ◽  
Nancy Chiang ◽  
Micah Steffek ◽  
Christine Kugel ◽  
Tristan I. Croll ◽  
...  
Keyword(s):  
Structural Model ◽  
Structure And Function ◽  
Antigen Binding ◽  
Surface Markers ◽  
Cell Surface Markers ◽  
Therapeutic Monoclonal Antibody ◽  
Cross Links ◽  
Cell Membrane Protein ◽  
And Function ◽  
Cluster Of Differentiation

Cluster of differentiation 20 (CD20) is a B cell membrane protein that is targeted by monoclonal antibodies for the treatment of malignancies and autoimmune disorders but whose structure and function are unknown. Rituximab (RTX) has been in clinical use for two decades, but how it activates complement to kill B cells remains poorly understood. We obtained a structure of CD20 in complex with RTX, revealing CD20 as a compact double-barrel dimer bound by two RTX antigen-binding fragments (Fabs), each of which engages a composite epitope and an extensive homotypic Fab:Fab interface. Our data suggest that RTX cross-links CD20 into circular assemblies and lead to a structural model for complement recruitment. Our results further highlight the potential relevance of homotypic Fab:Fab interactions in targeting oligomeric cell-surface markers.

scholarly journals Structural changes during HCN channel gating defined by high affinity metal bridges

2012 ◽  
Vol 140 (3) ◽  
pp. 279-291 ◽  
Author(s):  
Daniel C.H. Kwan ◽  
David L. Prole ◽  
Gary Yellen
Keyword(s):  
Structural Changes ◽  
Structural Model ◽  
Channel Gating ◽  
Structural Basis ◽  
Hcn Channels ◽  
Hcn Channel ◽  
Membrane Hyperpolarization ◽  
Linker Region ◽  
High Affinity ◽  
Gating Mechanism

Hyperpolarization-activated cyclic nucleotide–sensitive nonselective cation (HCN) channels are activated by membrane hyperpolarization, in contrast to the vast majority of other voltage-gated channels that are activated by depolarization. The structural basis for this unique characteristic of HCN channels is unknown. Interactions between the S4–S5 linker and post-S6/C-linker region have been implicated previously in the gating mechanism of HCN channels. We therefore introduced pairs of cysteines into these regions within the sea urchin HCN channel and performed a Cd2+-bridging scan to resolve their spatial relationship. We show that high affinity metal bridges between the S4–S5 linker and post-S6/C-linker region can induce either a lock-open or lock-closed phenotype, depending on the position of the bridged cysteine pair. This suggests that interactions between these regions can occur in both the open and closed states, and that these regions move relative to each other during gating. Concatenated constructs reveal that interactions of the S4–S5 linker and post-S6/C-linker can occur between neighboring subunits. A structural model based on these interactions suggests a mechanism for HCN channel gating. We propose that during voltage-dependent activation the voltage sensors, together with the S4–S5 linkers, drive movement of the lower ends of the S5 helices around the central axis of the channel. This facilitates a movement of the pore-lining S6 helices, which results in opening of the channel. This mechanism may underlie the unique voltage dependence of HCN channel gating.

Microscale Structural Model of Alzheimer's Aβ(1-40) Amyloid Fibril: Comparative Study of 2- and 3-fold Morphologies

2009 ◽  
Vol 1240 ◽  
Author(s):  
Raffaella Paparcone ◽  
Markus J Buehler
Keyword(s):  
Structural Changes ◽  
Amyloid Fibrils ◽  
Structural Model ◽  
Amyloid Fibril ◽  
Physical Models ◽  
Structural Basis ◽  
Stable Configuration ◽  
Pathological Feature ◽  
Amyloid Fibers ◽  
Degenerative Disorders

AbstractAmyloid fibrils aggregation is a key pathological feature of many severe degenerative disorders including Alzheimer’s disease and clinical dementia. Moreover, amyloids have been classified as intriguing molecules due to their exceptional strength, sturdiness and elasticity. However, physical models that explain the structural basis of these properties remain largely elusive, preventing the description of the link between their hierarchical structure and physical properties. Here we present an atomistic-based multiscale analysis based on computational materiomics, utilized to predict the structure of the two known polymorphous Alzheimer’s Aβ(1–40) amyloid fibers. We report an analysis of the energies, structural changes and H-bonding for varying amyloid fibril lengths, elucidating their size dependent properties. We also propose an explanation for the different stability of the two morphologies. A structural model of amyloid fibers with lengths of hundreds of nanometers at atomistic resolution is obtained. It predicts the formation of twisted amyloid microfibers in close agreement with experimental results. The approach used here provides a link between the fibril geometry, the chemical interactions and the most stable configuration, and resolves the issue of missing atomistic structures for long amyloid fibers.

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