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Congenital and acquired disorders of coagulation
Published in Jennifer Duguid, Lawrence Tim Goodnough, Michael J. Desmond, Transfusion Medicine in Practice, 2020
Jeanne M Lusher, Roshni Kulkarni
VWF circulates as a series of multimers of increasing size, the largest having a molecular weight of 20 000 kDa. The multimers consist of protomers of about 500 kDa; each protomer is made up of two identical subunits of 220 kDa. This repeating structure provides a large number of binding sites, allowing vWF to serve as a bridge between platelets, and between platelets and injury sites in the vessel wall. The multimeric structure of VWF can be visualized by multimeric analysis; utilizing electrophoresis of plasma in SDS gels, and autoradiography, one can observe the variant structures of VWF.
The Chemical Cross-Linking Of Peptide Chains
Published in Roger L. Lundblad, Chemical Reagents for Protein Modification, 2020
Homobifunctional imidoesters (Figure 8) were introduced by Singer and co-workers.47 These reagents have the advantage that the reaction with the protein results in charge preservation of the lysine residue modified. This class of reagents is highly specific for primary amines in the following reactions as shown in Figures 9 and 10. Aspects of the chemistry of this reaction are discussed further in Chapter 10. Buffer effects on the reaction have not been extensively investigated except to specify that the use of potential competing nucleophiles (e.g., Tris, imidazole) should be avoided. Most studies have used 0.02 to 0.1 M triethanolamine in the range of pH 8.0 to 9.0. It has been suggested that the amidation reaction is enhanced by the presence of triethanolamine in studies on the reaction of methyl-4-mercaptobutyrimidate.31 The greatest use of these reagents has been in the study of protomer organization of oligomeric proteins and self-association systems.
The Structure of Pyruvate Carboxylase
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
John C. Wallace, Simon B. Easterbrook-Smith
However, the model proposed by Cohen et al.194 for yeast pyruvate carboxylase is fundamentally different. After considering a number of computer-generated alternatives, these authors chose a model in which ellipsoidal subunits are arranged with their centers located in the same plane at the corners of a rhombus, but with the diagonally opposite pairs of subunits aligned in orthogonal planes (see Figure 8). This configuration implies either that the subunits are of two different types or that each of the apparently identical subunits has four different bonding domains (see Figure 9), two of which are unoccupied. The presence of functional unoccupied binding sites could facilitate polymerization of the tetramer to larger-molecular-weight forms, but there is no evidence for such an occurrence. On the other hand, the subunits of yeast pyruvate carboxylase are indistinguishable on the basis of size or overall charge, all contain biotin, and all have blocked N-termini.194 Though it remains to be proven that these protomers are identical, they clearly are very similar (see also Section III.H).
Epidemiology, pathogenesis, clinical presentations, diagnosis and treatment of COVID-19: a review of current evidence
Published in Expert Review of Clinical Pharmacology, 2021
Sayeeda Rahman, Maria Teresa Villagomez Montero, Kherie Rowe, Rita Kirton, Frank Kunik
Coronaviruses get their name from the characteristic feature of their S protein, which resembles a halo effect seen in solar eclipse or a crown-like appearance under an electron microscope [34]. The S protein has a roughly cylindrical shape and is heavily glycosylated [40], and encodes and possesses both receptor-binding and-fusion functions. Coronavirus uses its S protein, a main target for neutralizing antibodies, to bind with specific receptors and mediate membrane fusion and virus entry. It is a trimeric protein [34], composed of three intertwined chains that have identical amino acid sequences, each of which is called a protomer. However, the protomers do not have identical three-dimensional conformations. The monomer of the trimeric S protein is approximately 180 kDa and contains two distinct functional subunits, S1 and S2, both necessary for mediating attachment and membrane fusion, respectively. In its structure, N- and C-terminal portions of the S1 fold are two independent domains, the N-terminal domain (NTD) and C-terminal domain (CTD). Depending on the virus, either NTD or CTD can serve as the receptor-binding domain (RBD). The S protein induces successful infusion into the cell by first binding to the host receptor through the RBD of the S1 subunit, resulting in viral genomic fusion; the second stage by S2 facilitates the fusion of the cell and host membranes, which contains amino acid sequences necessary for continuing infiltration [41–43]. The RBD in the S protein is the most mutable part of the coronavirus genome and tends to be common for general viruses [44].
Role of vacuolating cytotoxin A in Helicobacter pylori infection and its impact on gastric pathogenesis
Published in Expert Review of Anti-infective Therapy, 2020
Shamshul Ansari, Yoshio Yamaoka
VacA oligomerization is important for insertion into the lipid membrane bilayer to form ion channels. After its secretion, VacA assembles into water-soluble single-layer or double-layer flower-shaped oligomers that contain six (hexamer) or seven (heptamer) copies of protomers [13,16]. Structural analysis has shown that the angle of protomer–protomer interactions is the major difference between hexamers and heptamers, with a larger binding interface in hexamers than in heptamers [61]. A recent study suggests that the water-soluble VacA oligomer first dissociates into monomers at the low pH conditions provided in the gastric lumen. Here, these monomers bind to the host cell membrane, insert into the lipid bilayer, oligomerize, and finally form membrane channels [62]. For oligomerization, the protomers interact via the residues present in both the p33 and p55 domains. As the structure of VacA is mostly rolling β-strands connected by flexible loops, an extended loop in the p55 domain of one protomer contacts the p33 domain of the adjacent protomer, and an α-helix is sandwiched between the protomers [61].
The extracellular matrix of the blood–brain barrier: structural and functional roles in health, aging, and Alzheimer’s disease
Published in Tissue Barriers, 2019
May J. Reed, Mamatha Damodarasamy, William A. Banks
Collagen type IV (Col IV) is the most abundant fibrous protein within the interstitial ECM and is secreted by ECs, astrocytes, and pericytes in brain vasculature.100 In other tissues, Col IV is essential for regulating cell adhesion and directing tissue development through its role in chemotaxis and cell migration, while also providing strength to the ECM.101 Col IV consists of polypeptide chains derived from six different α chains, which can combine and form three different collagen IV isoforms. The Col IV isoform predominantly expressed in the brain consists of two α1 and one α2 chains that fuse to form the collagen IV [a 1(IV)]2a 2(IV) isoforms.87 Inside cells, the three alpha-chains assemble forming triple helical molecules, termed protomers, which oligomerize outside the cells into a supramolecular network.102 The self-assembly of the Col IV protomers is associated with both lateral (side-by-side) as well as C- and N-terminal non-covalent bindings of the Col IV monomers.102 Col IV stabilizes BM by retaining laminin and other ECM proteins, such as nidogen, and perlecan. Modest mutations in the Col4α1 gene are associated with fragile vessels that predispose to stress-induced hemorrhage and adult-onset stroke in humans.103,104 Null mutations of Col IV in mice are embryonic lethal due, in part, to impaired BM stability.105