Daniel C. Hoessli

BRAF gene: From human cancers to developmental syndromes

The BRAF gene encodes for a serine/threonine protein kinase that participates in the MAPK/ERK signalling pathway and plays a vital role in cancers and developmental syndromes (RASopathies). The current review discusses the clinical significance of the BRAF gene and other members of RAS/RAF cascade in human cancers and RAS/MAPK syndromes, and focuses the molecular basis and clinical genetics of BRAF to better understand its parallel involvement in both tumourigenesis and RAS/MAPK syndromes—Noonan syndrome, cardio-facio-cutaneous syndrome and LEOPARD syndrome.

N-acetylgalactosaminyltransferases in cancer.

Aberrant mucin-type O-glycosylation by glycosyltransferases is a well-described hallmark of many cancers and is also associated with additional non-cancerous developmental and metabolic disorders. The current review focuses on N-acetylgalactosaminyltransferase genes (GALNTs) and proteins (GalNAcTs) to illustrate their importance in cancer biology. Aberrant O-glycosylation by GalNAcTs activates a wide range of proteins that carry out interactions of sessile and motile cells affecting organogenesis, responses to agonists and stimulating hyperproliferation and metastatisation of neoplastic cells. As genome-wide analyses have provided abundant clues regarding under- or over-expressed genes that characterize different types of cancers, GALNTs and their transferase products have attracted attention by being unexpected actors in neoplastic contexts. We intend to review the current knowledge on GALNTs and their encoded transferases in cancer and suggest what could be the significance of such information in cancer pathogenesis and management.

Mechanistic understanding and significance of small peptides interaction with MHC class II molecules for therapeutic applications.

Major histocompatibility complex (MHC) class II molecules are expressed by antigen‐presenting cells and stimulate CD4+ T cells, which initiate humoral immune responses. Over the past decade, interest has developed to therapeutically impact the peptides to be exposed to CD4+ T cells. Structurally diverse small molecules have been discovered that act on the endogenous peptide exchanger HLA‐DM by different mechanisms. Exogenously delivered peptides are highly susceptible to proteolytic cleavage in vivo; however, it is only when successfully incorporated into stable MHC II–peptide complexes that these peptides can induce an immune response. Many of the small molecules so far discovered have highlighted the molecular interactions mediating the formation of MHC II–peptide complexes. As potential drugs, these small molecules open new therapeutic approaches to modulate MHC II antigen presentation pathways and influence the quality and specificity of immune responses. This review briefly introduces how CD4+ T cells recognize antigen when displayed by MHC class II molecules, as well as MHC class II–peptide‐loading pathways, structural basis of peptide binding and stabilization of the peptide–MHC complexes. We discuss the concept of MHC‐loading enhancers, how they could modulate immune responses and how these molecules have been identified. Finally, we suggest mechanisms whereby MHC‐loading enhancers could act upon MHC class II molecules.

Influence of the sequence environment and properties of neighboring amino acids on amino-acetylation: relevance for structure-function analysis.

Proteins function is regulated by co‐translational modifications and post‐translational modifications (PTMs) such as phosphorylation, glycosylation, and acetylation, which induce proteins to perform multiple tasks in a specified environment. Acetylation takes place post‐translationally on the ε‐amino group of Lys in histone proteins, allowing regulation of gene expression. Furthermore, amino group acetylation also occurs co‐translationally on Ser, Thr, Gly, Met, and Ala, possibly contributing to the stability of proteins. In this work, the influence of amino acids next to acetylated sites has been investigated by using MAPRes (Mining Association Patterns among preferred amino acid residues in the vicinity of amino acids targeted for PTMs). MAPRes was utilized to examine the sequence patterns vicinal to modified and non‐modified residues, taking into account their charge and polarity. The PTMs data were further sub‐divided according to their sub‐cellular location (nuclear, mitochondrial, and cytoplasmic), and their association patterns were mined. The association patterns mined by MAPRes for acetylated and non‐acetylated residues are consistent with the existing literature but also revealed novel patterns. These rules have been utilized to describe the acetylation and its effects on the protein structure‐function relationship. J. Cell. Biochem. 114: 874–887, 2013.

O-GlcNAc modification of the anti-malarial vaccine candidate PfAMA1: in silico-defined structural changes and potential to generate a better vaccine.

The complex life cycle of plasmodial parasites makes the selection of a single subunit protein a less than optimal strategy to generate an efficient vaccinal protection against malaria. Moreover, the full protection afforded by malarial proteins carried by intact parasites implies that immune responses against different antigens expressed in different phases of the cycle are required, but also suggests that native malarial antigens are presented to the host immune system in a manner that recombinant proteins do not achieve. The malarial apical membrane antigen 1 (AMA1) represents a suitable vaccine candidate because AMA1 is expressed on sporozoites and merozoites and allows them to invade hepatocytes and erythrocytes, respectively. Anti-AMA1 antibodies and cytotoxic T-cells are therefore expected to interfere both with the primary invasion of hepatocytes by sporozoites and with the later propagation of merozoites in erythrocytes, and thus efficiently counteract parasite development in its human host. AMA1 bears potential glycosylation sites and the human erythrocytic O-linked N-acetylglucosamine transferase (OGT) could glycosylate AMA1 through combinatorial metabolism. This hypothesis was tested in silico by developing binding models of AMA1 with human OGT complexed with UDP-GlcNc, and followed by the binding of O-GlcNAc with the hydroxyl group of AMA1 serine and threonine residues. Our results suggests that AMA1 shows potential for glycosylation at Thr517 and Ser498 and that O-GlcNAc AMA1 may constitute a conformationally more appropriate antigen for developing a protective anti-malarial immune response.

Charge and Polarity Preferences for N-Glycosylation: A Genome-Wide In Silico Study and Its Implications Regarding Constitutive Proliferation and Adhesion of Carcinoma Cells

The structural and functional diversity of the human proteome is mediated by N- and O-linked glycosylations that define the individual properties of extracellular and membrane-associated proteins. In this study, we utilized different computational tools to perform in silico based genome-wide mapping of 1,117 human proteins and unravel the contribution of both penultimate and vicinal amino acids for the asparagine-based, site-specific N-glycosylation. Our results correlate the non-canonical involvement of charge and polarity environment of classified amino acids (designated as L, O, A, P, and N groups) in the N-glycosylation process, as validated by NetNGlyc predictions, and 130 literature-reported human proteins. From our results, particular charge and polarity combinations of non-polar aliphatic, acidic, basic, and aromatic polar side chain environment of both penultimate and vicinal amino acids were found to promote the N-glycosylation process. However, the alteration in side-chain charge and polarity environment of genetic variants, particularly in the vicinity of Asn-containing epitope, may induce constitutive glycosylation (e.g., aberrant glycosylation at preferred and non-preferred sites) of membrane proteins causing constitutive proliferation and triggering epithelial-to-mesenchymal transition. The current genome-wide mapping of 1,117 proteins (2,909 asparagine residues) was used to explore charge- and polarity-based mechanistic constraints in N-glycosylation, and discuss alterations of the neoplastic phenotype that can be ascribed to N-glycosylation at preferred and non-preferred sites.

Editorial: Targeting Phosphorylation and Glycosylation of Membrane-Bound Oncogenic Drivers, Receptors and Adhesion Molecules to Control Constitutive Proliferation of Human Carcinoma Cells

Citation: Hussain MRM and Hoessli DC (2018) Editorial: Targeting Phosphorylation and Glycosylation of Membrane-Bound Oncogenic Drivers, Receptors and Adhesion Molecules to Control Constitutive Proliferation of Human Carcinoma Cells. Front. Oncol. 8:283. doi: 10.3389/fonc.2018.00283 Editorial: Targeting Phosphorylation and Glycosylation of Membrane-Bound Oncogenic Drivers, Receptors and Adhesion Molecules to Control Constitutive Proliferation of Human Carcinoma Cells