In this review, several of these aspects

Rapamycin in vivo will be discussed. In addition, the interaction of the FVIII/VWF complex with two families of carbohydrate-binding proteins, i.e. Galectins and Siglecs, and their potential physiological relevance will be discussed. Glycosylation is a posttranslation modification that is crucial for many members of the eukaryotic proteome, and involves the covalent attachment of carbohydrate structures to the protein backbone. Factor VIII (FVIII) and von Willebrand factor (VWF) are no exception in this regard as both proteins are highly glycosylated, and contain several N-linked and O-linked glycans (Fig. 1a,b). N-linked glycosylation refers to the linkage of carbohydrate structures to the terminal amide-group of Asn-residues present in the motif Asn-Xxx-Ser/Thr/Cys, where X is any amino acid but Pro. This process is initiated early during synthesis upon translocation of the protein into the ER lumen, and continues until after transportation to the Golgi apparatus. The commonly found mucin-type O-linked glycosylation involves the attachment of N-acetyl-galactosamine (GalNAc) moieties to Ser and Thr residues, a process that occurs at a later stage during synthesis,

when the protein selleck inhibitor has reached the Golgi. The presence of carbohydrate structures has several functions: to facilitate protein folding and intracellular routing, to improve solubility of proteins, to regulate enzymatic activity, to modulate immunogenic properties of proteins

and the mechanism by which they are cleared from the circulation. Indeed, many of these features also apply to FVIII and VWF (Table 1). Although one would expect that the presence of sugar structures is beneficial to these proteins, the opposite may be true as well. Indeed, being ‘too sweet’ is not always good for FVIII and VWF. The present review aims to focus on how glycosylation of FVIII and VWF affects the distinct steps within the life-cycle of both proteins in a positive and negative manner. In particular, learn more the interaction between both proteins and carbohydrate-binding proteins will be discussed. Analysis of the FVIII amino acid sequence reveals numerous consensus motifs allowing N-linked glycosylation, with the vast majority being located in the FVIII B-domain. A concise report on the structure of N-linked glycans present on plasma-derived FVIII (pd-FVIII) and recombinant full-length FVIII (rFVIII) appeared in 1992 [1]. For both molecules, the main carbohydrate structure consists of a complex-type biantennary core fucosylated oligosaccharide, a structure that is commonly found on secreted proteins (Fig. 1c). In addition, tri- and tetra-antennary structures as well as high mannose structures were identified.