Trends in Biochemical Sciences
Lectin control of protein folding and sorting in the secretory pathway
Section snippets
The calnexin cycle
Sequential action of glucosidase I, an integral membrane protein, and the soluble lumenal glucosidase II removes the two terminal glucose residues from the N-linked glycon, resulting in a Glc1-Man9-(GlcNAc)2 carbohydrate. Calnexin, an integral membrane chaperone, and its soluble lumenal counterpart, calreticulin, recognize specifically this singly glucosylated oligosaccharide and bind the glycoprotein (Fig. 1). The terminal glucose is essential for binding [10], but mannose residues can also
Calnexin and calreticulin structure
The crystal structure of the lumenal domain of calnexin reveals a highly asymmetric molecule (Fig. 2) comprising a globular lectin domain and a long hairpin loop, the so-called P-domain [18]. The P-domain can be divided into four modules, each formed by an antiparallel arrangement of two different proline-rich sequence motifs. The binding site for the terminal glucose moiety of the carbohydrate is located in the lectin domain. Sequence similarity between calnexin and calreticulin indicates that
Role of ERGIC-53 in glycoprotein sorting and ER–Golgi transport
Calnexin, ERGIC-53 and the homologous membrane protein VIP36 might participate in a chaperone–cargo receptor relay in the folding and transport of secretory glycoproteins. ERGIC-53 was first identified as a resident ER–Golgi intermediate compartment (ERGIC) protein [33]. Yeast orthologs of ERGIC-53 were recently identified [34] and amino acid sequence comparisons identified vesicular integral membrane protein 36 (VIP36) as a homolog of ERGIC-53 [35]. The similarity of these proteins to legume
Role of VIP36 in glycoprotein trafficking
Sequence similarity and secondary structure predictions indicate that VIP36 has a CRD similar to that of ERGIC-53 [35] and, like ERGIC-53, VIP36 is specific for high-mannose glycans [45]. Sequence alignments show that the aspartate residues implicated in Ca2+ and mannose binding in ERGIC-53 are conserved in VIP36. The precise role of VIP36 in glycoprotein sorting and transport remains uncertain. The highest concentration of VIP36 may be in the cis Golgi network [46]. However, VIP36
Structural comparison of calnexin and ERGIC-53 CRDs
The structural relationship between the molecular chaperone calnexin and the secretory cargo receptor ERGIC-53 has only recently come to light [39]. The lectin domain of calnexin and the CRD of ERGIC-53 are among a large group of structurally related lectins [39]. The SCOP classification 48, 49 places the lectin domain of calnexin in the concanavalin-A-like lectins/glucanases fold family. Among the other protein families included in this fold family are the β-glucanases, galectins, pentraxins
Substrates common to calnexin and ERGIC-53
Folding and secretion of coagulation factors V and VIII are known to occur via interactions with calnexin and/or calreticulin [50]. Factor VIII interacts with both calnexin and calreticulin, whereas factor V interacts only with calreticulin [51]. In the absence of glucose trimming, secretion of factor VIII is abolished. Secretion of both factor V and factor VIII is inhibited by mutations in ERGIC-53 that eliminate glycan binding or mutations that eliminate cycling of ERGIC-53 between the ER and
Other lectins in the secretory pathway
The repertoire of potential glycan-binding proteins in the ER is expanding rapidly. Alignment of the sequences of human mannose 6-phosphate receptor and the β-subunit of glucosidase II reveals the presence of a mannose 6-phosphate receptor homology domain in glucosidase, a domain known to recognize N-glycans [54]. The function of the β-subunit of glucosidase II is poorly understood, but it stabilizes the catalytic α-subunit [50] and provides the C-terminal ER-localization HDEL sequence. The
Summary
The structural similarities of calnexin, calreticulin, ERGIC-53 and VIP36 and their roles in the folding and secretion of glycoproteins suggest that homologous lectins are instrumental in the progression of glycoproteins through the secretory pathway. Mutations in the known individual components of this pathway affect secretion of only a subset of all glycoproteins. This suggests that either there are alternative secretory routes or that there exist several as yet unidentified lectins with
Acknowledgements
We gratefully acknowledge the support of the National Research Council of Canada, the Canada Institutes of Health Research, Genome Quebec and Genome Canada.
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