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.

scholarly journals Quantification of amyloid fibril polymorphism by nano-morphometry reveals the individuality of filament assembly

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Liam D. Aubrey ◽  
Ben J. F. Blakeman ◽  
Liisa Lutter ◽  
Christopher J. Serpell ◽  
Mick F. Tuite ◽  
...  
Keyword(s):  
Self Assembly ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Biological Function ◽  
Structural Basis ◽  
Distance Curve ◽  
Filament Assembly ◽  
Sample Heterogeneity ◽  
Structural Insights ◽  
Polymorphic Nature

Abstract Amyloid fibrils are highly polymorphic structures formed by many different proteins. They provide biological function but also abnormally accumulate in numerous human diseases. The physicochemical principles of amyloid polymorphism are not understood due to lack of structural insights at the single-fibril level. To identify and classify different fibril polymorphs and to quantify the level of heterogeneity is essential to decipher the precise links between amyloid structures and their functional and disease associated properties such as toxicity, strains, propagation and spreading. Employing gentle, force-distance curve-based AFM, we produce detailed images, from which the 3D reconstruction of individual filaments in heterogeneous amyloid samples is achieved. Distinctive fibril polymorphs are then classified by hierarchical clustering, and sample heterogeneity is objectively quantified. These data demonstrate the polymorphic nature of fibril populations, provide important information regarding the energy landscape of amyloid self-assembly, and offer quantitative insights into the structural basis of polymorphism in amyloid populations.

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.

scholarly journals Quantification of amyloid fibril polymorphism by nano-morphometry reveals the individuality of filament assembly

2020 ◽  
Author(s):  
Liam D. Aubrey ◽  
Ben J. F. Blakeman ◽  
Liisa Lutter ◽  
Christopher J. Serpell ◽  
Mick F. Tuite ◽  
...  
Keyword(s):  
Self Assembly ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Biological Function ◽  
Structural Basis ◽  
Force Curve ◽  
Filament Assembly ◽  
Sample Heterogeneity ◽  
Structural Insights ◽  
Polymorphic Nature

ABSTRACTAmyloid fibrils are highly polymorphic structures formed by many different proteins. They provide biological function but also abnormally accumulate in numerous human diseases. The physicochemical principles of amyloid polymorphism are not understood due to lack of structural insights at the single-fibril level. To identify and classify different fibril polymorphs and to quantify the level of heterogeneity is essential to decipher the precise links between amyloid structures and their functional and disease associated properties such as toxicity, strains, propagation and spreading. Employing gentle, force-curve based AFM, we produce detailed images, from which the 3D reconstruction of individual filaments in heterogeneous amyloid samples is achieved. Distinctive fibril polymorphs are then classified by hierarchical clustering, and sample heterogeneity is objectively quantified. These data demonstrate the polymorphic nature of fibril populations, provide important information regarding the energy landscape of amyloid self-assembly, and offer quantitative insights into the structural basis of polymorphism in amyloid populations.

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 Heparin Inhibits Cellular Invasion by SARS-CoV-2: Structural Dependence of the Interaction of the Spike S1 Receptor-Binding Domain with Heparin

2020 ◽  
Vol 120 (12) ◽  
pp. 1700-1715
Author(s):  
Courtney J. Mycroft-West ◽  
Dunhao Su ◽  
Isabel Pagani ◽  
Timothy R. Rudd ◽  
Stefano Elli ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Structural Changes ◽  
Rapid Development ◽  
Antiviral Agents ◽  
Vero Cells ◽  
Binding Domain ◽  
Microbial Pathogens ◽  
Minimum Size ◽  
Structural Basis ◽  
Receptor Binding Domain

AbstractThe dependence of development and homeostasis in animals on the interaction of hundreds of extracellular regulatory proteins with the peri- and extracellular glycosaminoglycan heparan sulfate (HS) is exploited by many microbial pathogens as a means of adherence and invasion. Heparin, a widely used anticoagulant drug, is structurally similar to HS and is a common experimental proxy. Exogenous heparin prevents infection by a range of viruses, including S-associated coronavirus isolate HSR1. Here, we show that heparin inhibits severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) invasion of Vero cells by up to 80% at doses achievable through prophylaxis and, particularly relevant, within the range deliverable by nebulisation. Surface plasmon resonance and circular dichroism spectroscopy demonstrate that heparin and enoxaparin, a low-molecular-weight heparin which is a clinical anticoagulant, bind and induce a conformational change in the spike (S1) protein receptor-binding domain (S1 RBD) of SARS-CoV-2. A library of heparin derivatives and size-defined fragments were used to probe the structural basis of this interaction. Binding to the RBD is more strongly dependent on the presence of 2-O or 6-O sulfate groups than on N-sulfation and a hexasaccharide is the minimum size required for secondary structural changes to be induced in the RBD. It is likely that inhibition of viral infection arises from an overlap between the binding sites of heparin/HS on S1 RBD and that of the angiotensin-converting enzyme 2. The results suggest a route for the rapid development of a first-line therapeutic by repurposing heparin and its derivatives as antiviral agents against SARS-CoV-2 and other members of the Coronaviridae.

scholarly journals Secondary Structural Model of MALAT1 Becomes Unstructured in Chronic Myeloid Leukemia and Undergoes Structural Rearrangement in Cervical Cancer

2021 ◽  
Vol 7 (1) ◽  
pp. 6
Author(s):  
Matthew C. Wang ◽  
Phillip J. McCown ◽  
Grace E. Schiefelbein ◽  
Jessica A. Brown
Keyword(s):  
Cervical Cancer ◽  
Chronic Myeloid Leukemia ◽  
Hela Cells ◽  
Binding Sites ◽  
Myeloid Leukemia ◽  
Structural Changes ◽  
Structural Model ◽  
Dimethyl Sulfate ◽  
K562 Cells ◽  
Cancer Types

Long noncoding RNAs (lncRNAs) influence cellular function through binding events that often depend on the lncRNA secondary structure. One such lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), is upregulated in many cancer types and has a myriad of protein- and miRNA-binding sites. Recently, a secondary structural model of MALAT1 in noncancerous cells was proposed to form 194 hairpins and 13 pseudoknots. That study postulated that, in cancer cells, the MALAT1 structure likely varies, thereby influencing cancer progression. This work analyzes how that structural model is expected to change in K562 cells, which originated from a patient with chronic myeloid leukemia (CML), and in HeLa cells, which originated from a patient with cervical cancer. Dimethyl sulfate-sequencing (DMS-Seq) data from K562 cells and psoralen analysis of RNA interactions and structure (PARIS) data from HeLa cells were compared to the working structural model of MALAT1 in noncancerous cells to identify sites that likely undergo structural alterations. MALAT1 in K562 cells is predicted to become more unstructured, with almost 60% of examined hairpins in noncancerous cells losing at least half of their base pairings. Conversely, MALAT1 in HeLa cells is predicted to largely maintain its structure, undergoing 18 novel structural rearrangements. Moreover, 50 validated miRNA-binding sites are affected by putative secondary structural changes in both cancer types, such as miR-217 in K562 cells and miR-20a in HeLa cells. Structural changes unique to K562 cells and HeLa cells provide new mechanistic leads into how the structure of MALAT1 may mediate cancer in a cell-type specific manner.

scholarly journals The Ultrastructure of Tissue Damage by Amyloid Fibrils

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4611
Author(s):  
Haruki Koike ◽  
Masahisa Katsuno
Keyword(s):  
Tissue Damage ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Prion Diseases ◽  
Nerve Biopsy ◽  
Al Amyloidosis ◽  
Amyloid Fibril Formation ◽  
Autopsy Specimens ◽  
Fibril Aggregates ◽  
Interfering Rna

Amyloidosis is a group of diseases that includes Alzheimer’s disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: 1) reducing or preventing the production of causative proteins; 2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or 3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.

scholarly journals Structural basis for a complex I mutation that blocks pathological ROS production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhan Yin ◽  
Nils Burger ◽  
Duvaraka Kula-Alwar ◽  
Dunja Aksentijević ◽  
Hannah R. Bridges ◽  
...  
Keyword(s):  
Point Mutation ◽  
Complex I ◽  
Structural Changes ◽  
Ischemia Reperfusion ◽  
Single Point ◽  
Structural Basis ◽  
Single Point Mutation ◽  
Ros Production

AbstractMitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the “deactive” state, usually formed only after prolonged inactivity. Despite its tendency to adopt the “deactive” state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.

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.

New insights into the structural basis of integrin activation

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1155-1159 ◽  
Author(s):  
Jian-Ping Xiong ◽  
Thilo Stehle ◽  
Simon L. Goodman ◽  
M. Amin Arnaout
Keyword(s):  
Conformational Changes ◽  
Structural Changes ◽  
Structural Basis ◽  
Integrin Activation ◽  
Cellular Functions ◽  
Electron Microscopic ◽  
The Past ◽  
Intracellular Signals ◽  
Bidirectional Signaling ◽  
New Hypothesis

Abstract Integrins are cell adhesion receptors that communicate biochemical and mechanical signals in a bidirectional manner across the plasma membrane and thus influence most cellular functions. Intracellular signals switch integrins into a ligand-competent state as a result of elicited conformational changes in the integrin ectodomain. Binding of extracellular ligands induces, in turn, structural changes that convey distinct signals to the cell interior. The structural basis of this bidirectional signaling has been the focus of intensive study for the past 3 decades. In this perspective, we develop a new hypothesis for integrin activation based on recent crystallographic, electron microscopic, and biochemical studies.

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