Nevertheless, the importance of FVIII binding to the LMAN1/MCFD2

Nevertheless, the importance of FVIII binding to the LMAN1/MCFD2 complex is illustrated by the combined FVIII and FV deficiency that is associated with genetic defects in the genes encoding these cargo proteins [12]. Once secreted into the circulation, FVIII is exposed to a broad spectrum of carbohydrate-binding proteins. One of these is the asialoglycoprotein-receptor (ASGPR), which was identified as a potential receptor for FVIII [13]. ASGPR preferably interacts with terminal non-sialylated galactose-residues exposed in tri- and tetra-antennary glycan

structures [14]. Bovenschen et al. [13] ICG-001 in vitro demonstrated that full-length FVIII but not recombinant B-domainless FVIII is able to interact with ASGPR, suggesting that the high glycan density in the B-domain allows the interaction with this receptor. Despite the high affinity of the interaction (KD∼2 nm), the authors indicate that the physiological relevance of ASGPR in the clearance of FVIII is expected to be small. Instead, they propose a role for ASGPR regarding the premature clearance of hypo-sialylated FVIII molecules, thereby

adding an extracellular step to the already extensive quality control system for FVIII. Another Dasatinib datasheet carbohydrate-binding receptor that has been identified as a partner for FVIII is macrophage mannose receptor, also known as CD206 [15]. CD206 is an endocytic C-type lectin receptor that associates with exposed mannose residues in glycoproteins. Indeed, two high mannose glycan structures are present in FVIII (at positions Asn239 and Asn2118, respectively), which could mediate the interaction with CD206 [16]. The expression of CD206 in dendritic cells was found to support the uptake and subsequent presentation of FVIII peptides to CD4+ T-cells. These findings suggest a link between the glycosylation pattern of FVIII and the immunogenic properties of the molecule. Like FVIII, VWF is a glycoprotein containing both N- and O-linked glycans. The mature VWF subunit contains 12 N-linked glycans, while the VWF propeptide sequence indicates the presence of four additional glycosylation sites. Detailed analysis of the glycans

present on multimeric pd-VWF revealed that the main carbohydrate structure is similar to that found on the FVIII molecule: a complex-type biantennary core-fucosylated Dichloromethane dehalogenase glycan [17]. This structure represents ∼60% of all glycans on VWF, which would correspond to 7–8 per monomer. In addition, VWF also carries ABO blood-group related glycan structures, which represent 13% of all glycans (1–2 per monomer) [17,18]. The remaining carbohydrate structures include tri-and tetra-antennary structures. Recently, similar glycan structures were reported to be present on recombinant CHO-derived VWF (rVWF) that is currently in clinical development, except of course that the use of the CHO-production platform prevents the presence of ABO-glycan structures [19].

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