Abstract
ERGIC-53 and VIP36 are categorized as leguminous type (L-type) lectins, and they function as cargo receptors for trafficking certain N-linked glycoproteins in the secretory pathway in animal cells. They share structural similarities in their carbohydrate recognition domains (CRDs) but exhibit distinct sugar-binding specificities and affinities. VIP36 specifically interacts with the α1,2-linked D1 mannosyl arm without terminal glucosylation, while ERGIC-53 shows a broader specificity and lower binding affinity to the high-mannose-type oligosaccharides, irrespective of the presence or absence of the non-reducing terminal glucose residue at the D1 arm. In this study, we determined the crystal structure of ERGIC-53–CRD in complex with their binding partner, MCFD2 and the α1,2 mannotriose which corresponds to the trisaccharide of the D1 arm of high-mannose-type glycans. ERGIC-53 can interact with the D1 trimannosyl arm in two alternative modes, one of which is similar but distinct from that previously observed for VIP36. ERGIC-53 has a shallower sugar-binding pocket than VIP36 because of the single amino acid substitution, Asp-to-Gly. This enables ERGIC-53 to accommodate the non-reducing terminal glucose of the D1 arm in its CRD. In the other interaction mode, the 3-OH group of the terminal mannose was situated outward with respect to the sugar binding pocket, also enabling the Glcα1-3 linkage formation without steric hindrance. Our findings thus provide a structural basis for the broad sugar-binding specificity of the ERGIC-53/MCFD2 cargo receptor complex.
Highlights
N-linked oligosaccharides play important roles in the determination of glycoprotein fates in cells through interactions with a series of intracellular lectins [1,2,3,4,5,6,7]
Crystallographic data has recently been reported for ERGolgi intermediate compartment (ERGIC)-53–carbohydrate recognition domains (CRDs) in complex with a1,2-linked mannobiose [31], the way in which this lectin shows a broad specificity toward monoglucosylated high-mannose-type oligosaccharides remains elusive because position of the nonreducing terminal Man(D1) residue could not be unambiguously determined in the crystal structure
We present new crystal structures of ternary complexes of ERGIC-53–CRD formed with MCFD2 and a2Man2 or a1,2-linked mannotriose corresponding to Man(D1)-Man(C)-Man(4); Figure 1A
Summary
N-linked oligosaccharides play important roles in the determination of glycoprotein fates in cells through interactions with a series of intracellular lectins [1,2,3,4,5,6,7]. Crystallographic data has recently been reported for ERGIC-53–CRD in complex with a1,2-linked mannobiose (termed a2-Man2) [31], the way in which this lectin shows a broad specificity toward monoglucosylated high-mannose-type oligosaccharides remains elusive because position of the nonreducing terminal Man(D1) residue could not be unambiguously determined in the crystal structure.
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