The sugar-binding ability of ERGIC-53 is enhanced by its interaction with MCFD2

Kawasaki, Norihito; Ichikawa, Yoko; Matsuo, Ichiro; Totani, Kiichiro; Matsumoto, Naoki; Ito, Yukishige; Yamamoto, Kazuo

doi:10.1182/blood-2007-06-097022

Cited by 51 publications

(55 citation statements)

References 51 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These mutations cause amino acid substitutions in the first EF-hand motif (D81Yand D89A) and the second EF-hand motif (D122V, D129E, Y135N, and I136T/V). All the mutations except for Y135N have already been tested for in vitro and/or in vivo interactions with ERGIC-53 and shown to result in impaired binding (3,10,12,17). The present study also confirmed the negative effects of these mutations on the binding capability to ERGIC-53-CRD (Figs.…”

Section: Discussionsupporting

confidence: 76%

“…By contrast, the product of MCFD2 is a soluble luminal protein with two EF-hand Ca 2þ -binding motifs (9). It has been shown that MCFD2 interacts with the CRD of ERGIC-53 in a Ca 2þ -dependent manner (9)(10)(11). Accumulating evidence indicates that this complex recycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC) and thereby functions as a cargo receptor in the early secretory pathway of FV and FVIII (12).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency

Nishio

Kamiya

Mizushima

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Combined deficiency of coagulation factors V and VIII (F5F8D), an autosomal recessive disorder characterized by coordinate reduction in the plasma levels of factor V (FV) and factor VIII (FVIII), is genetically linked to mutations in the transmembrane lectin ERGIC-53 and the soluble calcium-binding protein MCFD2. Growing evidence indicates that these two proteins form a complex recycling between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment and thereby function as a cargo receptor in the early secretory pathway of FV and FVIII. For better understanding of the mechanisms underlying the functional coordination of ERGIC-53 and MCFD2, we herein characterize their interaction by x-ray crystallographic analysis in conjunction with NMR and ultracentrifugation analyses. Inspection of the combined data reveals that ERGIC-53-CRD binds MCFD2 through its molecular surface remote from the sugar-binding site, giving rise to a 1∶1 complex in solution. The interaction is independent of sugarbinding of ERGIC-53 and involves most of the missense mutation sites of MCFD2 so far reported in F5F8D. Comparison with the previously reported uncomplexed structure of each protein indicates that MCFD2 but not ERGIC-53-CRD undergoes significant conformational alterations upon complex formation. Our findings provide a structural basis for the cooperative interplay between ERGIC-53 and MCFD2 in capturing FV and FVIII.MCFD2 | ERGIC-53 | calcium-binding protein | cargo receptor | intracellular lectin C ombined deficiency of coagulation factors V and VIII (F5F8D) is an autosomal recessive disorder characterized by coordinate reduction in the plasma levels of factor V (FV) and factor VIII (FVIII) (1, 2) Extensive genetic analysis of F5F8D patients identified two genes that are associated with this disorder. Genetic mutations in LMAN1 account for approximately 70% of F5F8D families, whereas the remaining 30% families possess mutation in MCFD2 (3, 4). LMAN1 encodes the transmembrane lectin ERGIC-53 (ER-Golgi intermediate compound protein of 53 kDa) (5), which possesses a luminal carbohydrate recognition domain (CRD) with specificity for highmannose-type oligosaccharides (6, 7) and forms dimers or hexamers stabilized by disulfide bonds formed in its stalk domain (5, 8). By contrast, the product of MCFD2 is a soluble luminal protein with two EF-hand Ca 2þ -binding motifs (9). It has been shown that MCFD2 interacts with the CRD of ERGIC-53 in a Ca 2þ -dependent manner (9-11). Accumulating evidence indicates that this complex recycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC) and thereby functions as a cargo receptor in the early secretory pathway of FV and FVIII (12).To gain a better understanding of the molecular mechanisms underlying the sorting and trafficking of these coagulation factors, it is essential to shed light on the structural basis of the cooperative interplay between ERGIC-53 and MCFD2. The crystallographic data of the CRD of rat ERGIC-53 have revealed that it com...

show abstract

Section: Discussionsupporting

confidence: 76%

mentioning

confidence: 99%

Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency

Nishio

Kamiya

Mizushima

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The binding constant for CRD and MCFD2 is 1.6 Â 10 8 M [6] and for CRD and N-terminal truncated MCFD2 in the same order (unpublished data) so the limited 850 Å 2 surface area buried upon complex formation is surprising. The binding of MCFD2 does not induce any major structural changes in the CRD and thus it most probably acts as co-receptor in the transport of FV and FVIII by direct interaction with cargo rather than through modulation of the binding of cargo to the CRD.…”

Section: Discussionmentioning

confidence: 99%

“…FVIII interacts with the LMAN1/MCFD2 complex, while the B-domain deleted form of FVIII exhibits reduced binding [5]. LMAN1/MCFD2 complex formation and FVIII binding are calcium ion dependent [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of the LMAN1‐CRD/MCFD2 transport receptor complex provides insight into combined deficiency of factor V and factor VIII

et al. 2010

View full text Add to dashboard Cite

a b s t r a c t LMAN1 is a glycoprotein receptor, mediating transfer from the ER to the ER-Golgi intermediate compartment. Together with the co-receptor MCFD2, it transports coagulation factors V and VIII. Mutations in LMAN1 and MCFD2 can cause combined deficiency of factors V and VIII (F5F8D). We present the crystal structure of the LMAN1/MCFD2 complex and relate it to patient mutations. Circular dichroism data show that the majority of the substitution mutations give rise to a disordered or severely destabilized MCFD2 protein. The few stable mutation variants are found in the binding surface of the complex leading to impaired LMAN1 binding and F5F8D. Structured summary:MINT-7557086: lman1 (uniprotkb:P49257) and mcfd2 (uniprotkb:Q8NI22) bind (MI:0407) by X-ray crystallography (MI:0114)

show abstract

“…Regulatory mechanisms may incorporate pH or Ca 2ϩ gradients that exist between lumenal compartments of the early secretory pathway (44,45). Indeed biochemical studies on interactions between the ERGIC-53 cargo receptor and high mannose glycoproteins indicated that binding affinity is influenced by both pH and Ca 2ϩ concentrations in correlation with intracellular gradients (35,46). Alternatively clustering of cargo receptors by COPII coat subunits at ER exit sites could increase receptor affinities for cargo and then reverse ligand binding upon vesicle uncoating.…”

Section: Discussionmentioning

confidence: 99%

Molecular Dissection of Erv26p Identifies Separable Cargo Binding and Coat Protein Sorting Activities

Bue

Barlowe

2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

The sugar-binding ability of ERGIC-53 is enhanced by its interaction with MCFD2

Cited by 51 publications

References 51 publications

Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency

Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency

Crystal structure of the LMAN1‐CRD/MCFD2 transport receptor complex provides insight into combined deficiency of factor V and factor VIII

Molecular Dissection of Erv26p Identifies Separable Cargo Binding and Coat Protein Sorting Activities

Contact Info

Product

Resources

About