scholarly journals Cryo-EM structures of τ filaments from human brain

2021 ◽  
Author(s):  
Michel Goedert
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Human Brain ◽  
Binding Sites ◽  
Chronic Traumatic Encephalopathy ◽  
Corticobasal Degeneration ◽  
Atomic Structures ◽  
Positron Emission ◽  
Β Sheets ◽  
Positron Emission Tomography Ligand

Abstract Electron cryo-microscopy (cryo-EM) has made it possible to determine near-atomic structures of τ filaments from human brain. Previous work had shown that the cores of paired helical and straight filaments of Alzheimer’s disease are made of two identical, but differently arranged C-shaped protofilaments. In recent years, cryo-EM has shown that the Alzheimer τ fold is 79 amino acids long. Five of the eight β-strands give rise to two antiparallel β-sheets, with the other three forming a β-helix. High-affinity binding sites of positron emission tomography ligand APN-1607 (PM-PBB3) are in the β-helix region. The Alzheimer fold contrasts with the 94 amino acid-long Pick fold, which is J-shaped and comprises nine β-strands that give rise to four antiparallel β-sheets, in the absence of a β-helix. Chronic traumatic encephalopathy τ fold is similar to the Alzheimer fold, but differs in the β-helix region, which is larger and contains a non-proteinaceous density that is probably hydrophobic. These folds are mostly two-layered. By contrast, the 107 amino acid τ fold of the 4R tauopathy corticobasal degeneration is four-layered and comprises 11 β-strands. It contains an internal, probably hydrophilic, density that is surrounded by τ. The τ folds described here share the presence of microtubule-binding repeats 3 and 4, as well as 10–13 amino acids after repeat 4.

Inhibition ofL-{18F}fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography

1986 ◽  
Vol 20 (2) ◽  
pp. 258-262 ◽  
Author(s):  
K. L. Leenders ◽  
W. H. Poewe ◽  
A. J. Palmer ◽  
D. P. Brenton ◽  
R. S. J. Frackowiak
Keyword(s):  
Amino Acids ◽  
Positron Emission Tomography ◽  
Human Brain ◽  
Emission Tomography ◽  
Positron Emission

scholarly journals Structural Analysis of Four Newly Identified Extracellular Membrane-Proximal Missense Mutations in Patients with Glanzmann Thrombasthenia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1452-1452
Author(s):  
Xavier Pillois ◽  
Mathieu Fiore ◽  
Alan Nurden
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Conflicts Of Interest ◽  
Severe Bleeding ◽  
Type I ◽  
Missense Mutations ◽  
Glanzmann Thrombasthenia ◽  
Activated State ◽  
Platelet Disorder ◽  
Β Sheets

Abstract Background: Glanzmann thrombasthenia (GT), an autosomal recessive inherited platelet disorder, is a moderate to severe bleeding syndrome caused by the absence of platelet aggregation due to quantitative and/or qualitative deficiencies of the αIIbβ3 integrin. We recently identified 41 causative missense mutations of which 24 were novel in a large cohort of 76 GT families (Genoscope project). These mutations mainly localize to the headpiece region of the integrin that has been well studied but 4 mutations although extracellular were proximal to the plasma membrane. We therefore performed molecular modeling of these 4 mutations to obtain new insights into the structure of a poorly understood region of this unique receptor. Aim: To identify structures or conformations engaged in the stability of the integrin and which are important for maturation and expression. Results: Of the 4 novel selected mutations, 3 concerned the calf-2 domain of αIIb - Gly792Glu (G823E, nomenclature with leader sequence), Leu924Gln (L955Q) and Thr953Lys (T984K) and one the EGF-3 domain of β3 Gly540Asp (G566D). All of these mutations affected highly conserved amino acids and were predicted to be damaging by in silico analysis (SIFT, Polyphen). None influenced glycosylation or mRNA splicing. They were present either in a homozygous form (β3 G540D) or were heterozygous in association with an identified and proven null mutation. Three were associated with type I GT (<5% αIIbβ3), while the αIIbG792E mutation occurred in a patient with type II GT (with 10% residual αIIbβ3) whose much reduced but partial transport to the surface was confirmed following expression of the recombinant integrin in CHO cells (with pro-αIIb predominating in the cytoplasm). The structural implications of these amino acid substitutions was assessed using PyMol Molecular Graphics System version 1.3 (www.pymol.org) based on the crystallographic data of αIIbβ3 in the bent non-activated state (3fcs PDB file). Amino acids were visualized in the rotamer form showing side change orientations incorporated from the Dunbrack Backbone library with the maximum probability. We first determined that the αIIb calf-2 domain has a β barrel-like structure largely composed of hydrophobic amino acids whose side chains orientate towards the inner cavity. Interestingly, L924Q and T953K substitutions occur at or adjacent to a conserved motif consisting of five polar amino acids central to the β barrel protected from H2O molecules and involved in H-bond interactions. This particular motif, specific to calf-2, may introduce rigidity close to the membrane. Both L924Q and T953K disrupt the β barrel motif and promote flexibility. G792E is situated between the calf-1 and calf-2 domains in an unstructured connecting loop between two adjacent β sheets. Its replacement by the larger negatively charged Glu introduces steric encumbrance and results in an increase of the angle formed by the two calf domains, probably leading to the straightening of the second distal part of the long arm of αIIb. The β3 G540D substitution is found in the EGF3 domain of β3 that occurs at the axe of the cysteine-rich domain of the β3 arm, facing the αIIb calf-1 and calf-2 domains in the intact integrin. This substitution with the introduction of a charged and larger amino acid results in a weaker link between the two β sheets of EGF-3 and a loss of H-bonds. The result is an increased fragility within the β3 arm structure notably at the site of two stacked aromatic amino acids (H539 and W553) with a moving apart of the β sheets. Conclusions: We show that 4 novel missense mutations in the extracellular membrane-proximal domains of αIIb and β3 cause conformational changes in domains that control the overall structure of the newly formed integrin. They show how the structure of both domains is under tight quality control and that precisely defined conformations are indispensable for αIIbβ3 maturation. Disclosures No relevant conflicts of interest to declare.

scholarly journals miR-1322 Binding Sites in Paralogous and Orthologous Genes

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Raigul Niyazova ◽  
Olga Berillo ◽  
Shara Atambayeva ◽  
Anna Pyrkova ◽  
Aigul Alybayeva ◽  
...  
Keyword(s):  
Amino Acids ◽  
Transcription Factors ◽  
Amino Acid ◽  
Binding Site ◽  
Binding Sites ◽  
Target Genes ◽  
Amino Acid Sequences ◽  
Orthologous Genes ◽  
Start Position ◽  
Human Genes

We searched for 2,563 microRNA (miRNA) binding sites in 17,494 mRNA sequences of human genes. miR-1322 has more than 2,000 binding sites in 1,058 genes withΔG/ΔGmratio of 85% and more. miR-1322 has 1,889 binding sites in CDSs, 215 binding sites in 5′ UTRs, and 160 binding sites in 3′ UTRs. From two to 28 binding sites have arranged localization with the start position through three nucleotides of each following binding site. The nucleotide sequences of these sites in CDSs encode oligopeptides with the same and/or different amino acid sequences. We found that 33% of the target genes encoded transcription factors. miR-1322 has arranged binding sites in the CDSs of orthologousMAMLD1,MAML2, andMAML3genes. These sites encode a polyglutamine oligopeptide ranging from six to 47 amino acids in length. The properties of miR-1322 binding sites in orthologous and paralogous target genes are discussed.

Recent Investigations on the Chemical Nature of Thromboplastin (“TP”) from Human Brain

1969 ◽  
Vol 21 (03) ◽  
pp. 534-545 ◽  
Author(s):  
E Hecht ◽  
G Wijngaards
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Human Brain ◽  
Chemical Nature ◽  
Lipid Fraction ◽  
Subsequent Paper ◽  
Human Brain Tissue ◽  
Small Peptides ◽  
Protein Moiety ◽  
Long Chain

SummaryIt was confirmed that purified thromboplastin from human brain tissue contains about 18 amino acids after hydrolysis.The following observations gave rise to a discussion if these amino acids are to be considered as contaminations only, or if they derived from a protein moiety of brain thromboplastin.The amino acids are present in all fractions of the thromboplastin and in the wash solutions, and their amount is very small.The amino acids cannot be removed from thromboplastin with the usual techniques, but amino acids and peptides added on purpose can be separated again.Investigations with DNFB pointed to the presence of a great number of precipitable small peptides of various composition. The possibility of the presence of a microamount of a long-chain peptide, or even a trace of protein could not be excluded.Four techniques to separate the amino acid-rich fraction of thromboplastin were studied, described, and the results obtained compared. Sephadex G-25 was most successful, and the fractions were analysed.Most striking was the percentage of aspartic acid in the non-lipid fraction, which is 13-26 times lower than that of proteins and lipoproteins.The biological investigations of these fractions are subject of the subsequent paper.

scholarly journals Statistical Evidence for a Helical Nascent Chain

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 357
Author(s):  
Leonor Cruzeiro ◽  
Andrew C. Gill ◽  
J. Chris Eilbeck
Keyword(s):  
Amino Acids ◽  
Protein Folding ◽  
Amino Acid ◽  
Secondary Structures ◽  
Initial Structure ◽  
The Novel ◽  
Nascent Chain ◽  
Equilibrium Process ◽  
Β Sheets ◽  
Α Helix

We investigate the hypothesis that protein folding is a kinetic, non-equilibrium process, in which the structure of the nascent chain is crucial. We compare actual amino acid frequencies in loops, α-helices and β-sheets with the frequencies that would arise in the absence of any amino acid bias for those secondary structures. The novel analysis suggests that while specific amino acids exist to drive the formation of loops and sheets, none stand out as drivers for α-helices. This favours the idea that the α-helix is the initial structure of most proteins before the folding process begins.

scholarly journals Advances in D-Amino Acids in Neurological Research

2020 ◽  
Vol 21 (19) ◽  
pp. 7325 ◽  
Author(s):  
James M. Seckler ◽  
Stephen J. Lewis
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Nmda Receptor ◽  
Human Brain ◽  
Neurological Disorders ◽  
Review Article ◽  
Brain Chemistry ◽  
Concise Overview ◽  
Neurological Research ◽  
The Brain

D-amino acids have been known to exist in the human brain for nearly 40 years, and they continue to be a field of active study to today. This review article aims to give a concise overview of the recent advances in D-amino acid research as they relate to the brain and neurological disorders. This work has largely been focused on modulation of the N-methyl-D-aspartate (NMDA) receptor and its relationship to Alzheimer’s disease and Schizophrenia, but there has been a wealth of novel research which has elucidated a novel role for several D-amino acids in altering brain chemistry in a neuroprotective manner. D-amino acids which have no currently known activity in the brain but which have active derivatives will also be reviewed.

scholarly journals Structure of Tau filaments in Prion protein amyloidoses

2021 ◽  
Author(s):  
Grace I. Hallinan ◽  
Md Rejaul Hoq ◽  
Manali Ghosh ◽  
Frank S. Vago ◽  
Anllely Fernandez ◽  
...  
Keyword(s):  
Amino Acid ◽  
Prion Protein ◽  
Molecular Mechanisms ◽  
Chronic Traumatic Encephalopathy ◽  
Corticobasal Degeneration ◽  
Paired Helical Filaments ◽  
Striking Similarity ◽  
Amyloid Angiopathy ◽  
Amyloid Deposits ◽  
Primary Amino

AbstractIn human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann–Sträussler–Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

scholarly journals Residues within a conserved amino acid motif of domains 1 and 4 of VCAM-1 are required for binding to VLA-4.

1994 ◽  
Vol 125 (1) ◽  
pp. 215-222 ◽  
Author(s):  
R H Vonderheide ◽  
T F Tedder ◽  
T A Springer ◽  
D E Staunton
Keyword(s):  
Amino Acids ◽  
Cell Adhesion ◽  
Amino Acid ◽  
Adhesion Molecule ◽  
Binding Sites ◽  
Tumor Cell Line ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Conserved Motif ◽  
Late Antigen

Vascular cell adhesion molecule 1 (VCAM-1), a member of the Ig superfamily originally identified on activated endothelium, binds to the integrin very late antigen-4 (VLA-4), also known as alpha 4 beta 1 or CD49d/CD29, to support cell-cell adhesion. Studies based on cell adhesion to two alternatively spliced forms of VCAM-1 or to chimeric molecules generated from them and intercellular adhesion molecule-1 (ICAM-1) have demonstrated two VLA-4 binding sites on the predominate form of VCAM-1. Here, we studied VLA-4-dependent adhesion of the lymphoid tumor cell line Ramos to cells expressing wild type and mutant forms of VCAM-1. Results based on domain deletion mutants demonstrated the existence and independence of two VLA-4-binding sites located in the first and fourth domains of VCAM-1. Results based on amino acid substitution mutants demonstrated that residues within a linear sequence of six amino acids found in both domain 1 and 4 were required for VLA-4 binding to either domain. Five of these amino acids represent a conserved motif also found in ICAM domains. We propose that integrin binding to these Ig-like domains depends on residues within this conserved motif. Specificity of integrin binding to Ig-like domains may be regulated by a set of nonconserved residues distinct from the conserved motif.

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