Interleukin-1 beta (IL-1 beta)-converting enzyme cleaves the IL-1 beta precursor to mature IL-1 beta, an important mediator of inflammation. The identification of the enzyme as a unique cysteine protease and the design of potent peptide aldehyde inhibitors are described. Purification and cloning of the complementary DNA indicates that IL-1 beta-converting enzyme is composed of two nonidentical subunits that are derived from a single proenzyme, possibly by autoproteolysis. Selective inhibition of the enzyme in human blood monocytes blocks production of mature IL-1 beta, indicating that it is a potential therapeutic target.

A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes.

The initial stage of host cell infection by influenza A viruses (IAV) is mediated through interaction of the viral haemagglutinin (HA) with cell surface glycans. The binding requirement of IAVs for Galβ(1,4)Glc/ GlcNAc (lactose/lactosamine) glycans with a terminal α(2,6)-linked (human receptors) or α(2,3)-linked (avian receptors) N-acetylneuraminic residue commonly found on N-glycans, is well-established. However the role and significance of sialylated Galβ(1,3)GalNAc (core 1) epitopes that are typical O-glycoforms in influenza virus pathogenesis remains poorly detailed. Here we report a multidisciplinary study using NMR spectroscopy, virus neutralization assays and molecular modelling, into the potential for IAV to engage sialyl-Galβ(1,3)GalNAc O-glycoforms for cell attachment. H5 containing virus like particles (VLPs) derived from an H5N1 avian IAV strain show a significant involvement of the O-glycan-specific GalNAc residue, coordinated by a EQTKLY motif conserved in highly pathogenic avian influenza (HPAI) strains. Notably, human pandemic H1N1 influenza viruses shift the preference from 'human-like' α(2,6)-linkages in sialylated Galβ(1,4)Glc/GlcNAc fragments to 'avian-like' α(2,3)-linkages in sialylated Galβ(1,3)GalNAc without involvement of the GalNAc residue. Overall, our study suggests that sialylated Galβ(1,3)GalNAc as O-glycan core 1 glycoforms are involved in the influenza A virus life cycle and play a particularly crucial role during infection of HPAI strains.

/pdf/unravelling-the-role-of-o-glycans-in-influenza-a-virus-3770p8fq1z.pdf

Unravelling the Role of O-glycans in Influenza A Virus Infection

The superfamily of proteins containing C-type lectin-like domains (CTLDs) is a large group of extracellular Metazoan proteins with diverse functions. The CTLD structure has a characteristic double-loop ('loop-in-a-loop') stabilized by two highly conserved disulfide bridges located at the bases of the loops, as well as a set of conserved hydrophobic and polar interactions. The second loop, called the long loop region, is structurally and evolutionarily flexible, and is involved in Ca2+-dependent carbohydrate binding and interaction with other ligands. This loop is completely absent in a subset of CTLDs, which we refer to as compact CTLDs; these include the Link/PTR domain and bacterial CTLDs. CTLD-containing proteins (CTLDcps) were originally classified into seven groups based on their overall domain structure. Analyses of the superfamily representation in several completely sequenced genomes have added 10 new groups to the classification, and shown that it is applicable only to vertebrate CTLDcps; despite the abundance of CTLDcps in the invertebrate genomes studied, the domain architectures of these proteins do not match those of the vertebrate groups. Ca2+-dependent carbohydrate binding is the most common CTLD function in vertebrates, and apparently the ancestral one, as suggested by the many humoral defense CTLDcps characterized in insects and other invertebrates. However, many CTLDs have evolved to specifically recognize protein, lipid and inorganic ligands, including the vertebrate clade-specific snake venoms, and fish antifreeze and bird egg-shell proteins. Recent studies highlight the functional versatility of this protein superfamily and the CTLD scaffold, and suggest further interesting discoveries have yet to be made.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1742-4658.2005.05031.x

The C-type lectin-like domain superfamily

Chemical Diversity in the Sialic Acids and Related α-Keto Acids: An Evolutionary Perspective

Publisher Summary Aberrant glycosylation is the most common phenomenon associated with oncogenic transformation expressed in cell membranes of animal and human cancer cells. Such aberrant structures at the surface membranes may well be effective targets in prevention, diagnosis, and treatment of human cancer. Many of the aberrant glycosylation products can be recognized by specific MAbs as tumor-associated carbohydrate antigens. Many of these antigens have been identified as carbohydrates, thus there is increasing evidence that essentially all human cancers are characterized by aberrant glycosylation. Aberrant glycosylation as such may be the basis of inappropriate cell/cell and cell/matrix interactions that may be reflected in the abnormal cell social behavior of tumor cells, such as uncontrolled cell growth, invasiveness, and metastatic potential. Whatever the genetic or epigenetic basis of expression of aberrant glycosylation is, the phenomenon is of crucial importance in understanding the antisocial behavior of tumor cells as well as in practical applications in diagnosis and treatment of human cancer.

Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens

Isolation and characterization of a mannan-binding protein from rabbit liver

A serum lectin specific for mannose and N-acetylglucosamine residues was isolated from human serum to near homogeneity mainly by affinity chromatography on a column of Sepharose 4B-mannan. The lectin, called mannan-binding protein, was a glycine-rich protein with an apparent molecular size of approximately 600,000 daltons, and had a subunit structure consisting of a single component with an apparent molecular weight of 31,000. Binding of the isolated lectin to 125I-labeled mannan was dependent upon the presence of Ca2+, proportional to the protein added, and a reversible and saturable process. Scatchard plot analysis of binding data indicated the presence of a binding site with a dissociation constant of 2.3 X 10(-9) M and a maximum capacity of 4.3 pmol of 125I-labeled mannan per microgram of protein (2.6 mol of mannan per mol of the protein). The mannan-binding protein, is different from C-reactive protein (CRP) and amyloid P-component (SAP), both of which are serum components known to bind polysaccharides in the presence of Ca2+. A distinct binding activity toward mannan which did not require Ca2+ was attributed to immunoglobulins (IgG).

Isolation and Characterization of a Mannan-Binding Protein from Human Serum

The mechanism of carbohydrate-mediated complement activation by the serum mannan-binding protein.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1016/S0014-5793%2896%2901144-1

Accelerated evolution of crotalinae snake venom gland serine proteases

Serum mannan-binding protein (MBP), which is a lectin specific for mannose and N-acetylglucosamine and is known to activate complement via the classical pathway, has been revealed to have a complement-dependent bactericidal activity, as tested on rough strains of Escherichia coli, K-12 and B. The bacteria, which had been sensitized with purified human serum MBP in the presence of Ca2+, followed by incubation with guinea pig complement, showed a marked decrease of colony forming ability compared with those not sensitized with the lectin. The bactericidal effect depended on the concentrations of the lectin and complement. The C4-dependency of the reaction indicated that the complement-dependent bactericidal action by MBP is expressed through the classical pathway. The bacteria were aggregated by the lectin. Scatchard plot analysis of 125I-labeled MBP binding to the bacteria showed that the dissociation constant (Kd) and the maximum binding capacity were 6 x 10(-9) M and 30,000 molecules of MBP per cell, respectively. The binding was inhibited by mannose, N-acetylglucosamine, N-acetylmannosamine, L-fucose, manno-heptulose, and sedoheptulose, suggesting that MBP recognized L-glycero-D-manno-heptose and N-acetylglucosamine constituting the core oligosaccharide of the E. coli K-12 cell wall, and L-glycero-D-manno-heptose for E. coli B. These findings suggest the physiological significance of the serum lectin in host defense, being consistent with the avirulence of E. coli rough strains in mammals.

Ikuo Yamashina

Papers

Isolation and characterization of a mannan-binding protein from rabbit liver

Isolation and Characterization of a Mannan-Binding Protein from Human Serum

The mechanism of carbohydrate-mediated complement activation by the serum mannan-binding protein.

Accelerated evolution of crotalinae snake venom gland serine proteases

A serum lectin (mannan-binding protein) has complement-dependent bactericidal activity.