Publications by authors named "Amin Sagar"

To overcome their limited genetic capacity, numerous viruses encode multifunctional proteins. The birnavirus VP3 protein plays key roles during infection, including scaffolding of the viral capsid during morphogenesis, recruitment, and regulation of the viral RNA polymerase, shielding of the double-stranded RNA genome and targeting of host endosomes for genome replication, and immune evasion. The dimeric form of VP3 is critical for these functions.

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Systemic lupus erythematosus (SLE), commonly referred to as lupus, is a widely prevalent chronic autoimmune disease that can affect any organ system in the body. Although the pathogenesis of this disease is rather complex and poorly understood, ultimately there is an overproduction of multiple self-reactive antinuclear antibodies. These autoantibodies are one of the laboratory hallmarks of the diagnosis and disease activity of SLE.

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The incorporation of fluorinated amino acids into proteins provides new opportunities to study biomolecular structure-function relationships in an elegant manner. The available strategies to incorporate the majority of fluorinated amino acids are not site-specific or imply important structural modifications. Here, we present a chemical biology approach for the site-specific incorporation of three commercially available Cγ-modified fluoroprolines that has been validated using a non-pathogenic version of huntingtin exon-1 (HttExon-1).

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The adenosine di-phosphate (ADP) ribosylation factor (Arf) small guanosine tri-phosphate (GTP)ases function as molecular switches to activate signaling cascades that control membrane organization in eukaryotic cells. In Arf1, the GDP/GTP switch does not occur spontaneously but requires guanine nucleotide exchange factors (GEFs) and membranes. Exchange involves massive conformational changes, including disruption of the core β-sheet.

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Structural insight eludes on how full-length gelsolin depolymerizes and caps filamentous (F-)actin, while the same entity can nucleate polymerization of G-actins. Analyzing small angle X-ray scattering (SAXS) data, we deciphered assemblies which enable these contrasting processes. Mixing Ca-gelsolin with F-actin in high salt F-buffer resulted in depolymerization of ordered F-actin rods to smaller sized species which became monodispersed upon dialysis with low salt G-buffer.

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Tip-links in the inner ear convey force from sound and trigger mechanotransduction. Here, we present evidence that tip-links (collectively as heterotetrameric complexes of cadherins) function as force filters during mechanotransduction. Our force-clamp experiments reveal that the tip-link complexes show slip-ideal-slip bond dynamics.

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Coronary artery calcium (CAC) is the measure of subclinical coronary artery atherosclerosis most strongly associated with atherosclerotic cardiovascular disease (ASCVD) risk. However, CAC is rarely reported in the inpatient setting to guide chest pain management. We present a case of very high CAC in a 64-year-old woman with hypertension, type 2 diabetes, and hyperlipidemia presenting with dyspnea.

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Arrestin-dependent G protein-coupled receptor (GPCR) signaling pathway is regulated by the phosphorylation state of GPCR's C-terminal domain, but the molecular bases of arrestin:receptor interaction are to be further illuminated. Here we investigated the impact of phosphorylation on the conformational features of the C-terminal region from three rhodopsin-like GPCRs, the vasopressin V2 receptor (V2R), the growth hormone secretagogue or ghrelin receptor type 1a (GHSR), and the β2-adernergic receptor (β2AR). Using phosphomimetic variants, we identified pre-formed secondary structure elements, or short linear motifs (SLiMs), that undergo specific conformational transitions upon phosphorylation.

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To counter the emergence of β-lactamase (BL) mediated resistance, design of new β-lactamase inhibitors (BLIs) is critical. Many high-resolution crystallographic structures of BL complexed with BLIs are available. However, their impact on BLI design is struggling to keep pace with novel and emerging variants.

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Huntington's disease neurodegeneration occurs when the number of consecutive glutamines in the huntingtin exon-1 (HTTExon1) exceeds a pathological threshold of 35. The sequence homogeneity of HTTExon1 reduces the signal dispersion in NMR spectra, hampering its structural characterization. By simultaneously introducing three isotopically labeled glutamines in a site-specific manner in multiple concatenated samples, 18 glutamines of a pathogenic HTTExon1 with 36 glutamines were unambiguously assigned.

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The structural investigation of intrinsically disordered proteins (IDPs) requires ensemble models describing the diversity of the conformational states of the molecule. Due to their probabilistic nature, there is a need for new paradigms that understand and treat IDPs from a purely statistical point of view, considering their conformational ensembles as well-defined probability distributions. In this work, we define a conformational ensemble as an ordered set of probability distributions and provide a suitable metric to detect differences between two given ensembles at the residue level, both locally and globally.

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Cis and trans-interactions among cadherins secure multicellularity. While the molecular structure of trans-interactions of cadherins is well understood, work to identify the molecular cues that spread the cis-interactions two-dimensionally is still ongoing. Here, we report that transient, weak, yet multivalent, and spatially distributed hydrophobic interactions that are involved in liquid-liquid phase separations of biomolecules in solution, alone can drive the lateral-clustering of cadherin-23 on a membrane.

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Huntington's disease is a neurodegenerative disorder caused by a CAG expansion in the first exon of the HTT gene, resulting in an extended polyglutamine (poly-Q) tract in huntingtin (httex1). The structural changes occurring to the poly-Q when increasing its length remain poorly understood due to its intrinsic flexibility and the strong compositional bias. The systematic application of site-specific isotopic labeling has enabled residue-specific NMR investigations of the poly-Q tract of pathogenic httex1 variants with 46 and 66 consecutive glutamines.

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The structural characterization of polydisperse systems consisting of multiple coexisting species or conformations is very challenging or impossible with classical approaches. As a consequence, the structural bases of relevant questions related to protein folding, transient partner recognition, conformational transitions or fibrillation remain poorly understood. Small-Angle Scattering (SAS) techniques structurally probe species present in solution in a population-weighted manner, enabling the inspection of polydisperse systems.

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Article Synopsis
  • - The study investigates how disordered proteins, like the adenovirus E1A protein, maintain their essential functions despite having diverse sequences, focusing on the mechanism of functional selection.
  • - E1A competes with host factors to bind the retinoblastoma (Rb) protein, affecting cell cycle regulation, and this interaction is driven by specific binding motifs linked by a disordered region that ensures strong binding affinity.
  • - The authors introduce the concept of "conformational buffering," which describes how changes in amino acid composition and sequence length help maintain effective binding across various E1A linkers, indicating a broader principle applicable to many disordered proteins.
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Atomically precise gold nanoclusters are a fascinating class of nanomaterials that exhibit molecule-like properties and have outstanding photoluminescence (PL). Their ultrasmall size, molecular chemistry, and biocompatibility make them extremely appealing for selective biomolecule labeling in investigations of biological mechanisms at the cellular and anatomical levels. In this work, we report a simple route to incorporate a preformed Au nanocluster into a model bovine serum albumin (BSA) protein.

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Objectives: Ground-glass opacity (GGO)-a hazy, gray appearing density on computed tomography (CT) of lungs-is one of the hallmark features of SARS-CoV-2 in COVID-19 patients. This AI-driven study is focused on segmentation, morphology, and distribution patterns of GGOs.

Method: We use an AI-driven unsupervised machine learning approach called PointNet++ to detect and quantify GGOs in CT scans of COVID-19 patients and to assess the severity of the disease.

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The COVID-19 (coronavirus disease 2019) pandemic affected more than 186 million people with over 4 million deaths worldwide by June 2021. The magnitude of which has strained global healthcare systems. Chest Computed Tomography (CT) scans have a potential role in the diagnosis and prognostication of COVID-19.

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Escherichia coli is a Gram-negative bacterium that colonises the human intestine and virulent strains can cause severe diarrhoeal and extraintestinal diseases. The protein SslE is secreted by a range of pathogenic and commensal E. coli strains.

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In signaling proteins, intrinsically disordered regions often represent regulatory elements, which are sensitive to environmental effects, ligand binding, and post-translational modifications. The conformational space sampled by disordered regions can be affected by environmental stimuli and these changes trigger, vis a vis effector domain, downstream processes. The disordered nature of these regulatory elements enables signal integration and graded responses but prevents the application of classical approaches for drug screening based on the existence of a fixed three-dimensional structure.

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Intrinsically Disordered Proteins and Regions (IDPs/IDRs) are key components of a multitude of biological processes. Conformational malleability enables IDPs/IDRs to perform very specialized functions that cannot be accomplished by globular proteins. The functional role for most of these proteins is related to the recognition of other biomolecules to regulate biological processes or as a part of signaling pathways.

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Objectives: Ground-glass opacity (GGO) - a hazy, gray appearing density on computed tomography (CT) of lungs - is one of the hallmark features of SARS-CoV-2 in COVID-19 patients. This AI-driven study is focused on segmentation, morphology, and distribution patterns of GGOs.

Method: We use an AI-driven unsupervised machine learning approach called PointNet++ to detect and quantify GGOs in CT scans of COVID-19 patients and to assess the severity of the disease.

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Transient biomolecular interactions play crucial roles in many cellular signaling and regulation processes. However, deciphering the structure of these assemblies is challenging owing to the difficulties in isolating complexes from the individual partners. The additive nature of small-angle X-ray scattering (SAXS) data allows for probing the species present in these mixtures, but decomposition into structural and thermodynamic information is difficult.

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Von Willebrand Factor (vWF), a 300-kDa plasma protein key to homeostasis, is cleaved at a single site by multi-domain metallopeptidase ADAMTS-13. vWF is the only known substrate of this peptidase, which circulates in a latent form and becomes allosterically activated by substrate binding. Herein, we characterised the complex formed by a competent peptidase construct (AD13-MDTCS) comprising metallopeptidase (M), disintegrin-like (D), thrombospondin (T), cysteine-rich (C), and spacer (S) domains, with a 73-residue functionally relevant vWF-peptide, using nine complementary techniques.

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