8jpg

From Proteopedia

Cryo-EM structure of full-length ERGIC-53 with MCFD2

Structural highlights

8jpg is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 6.76Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

LMAN1_HUMAN Defects in LMAN1 are THE cause of factor V and factor VIII combined deficiency type 1 (F5F8D1) [MIM:227300; also known as multiple coagulation factor deficiency I (MCFD1). F5F8D1 is an autosomal recessive blood coagulation disorder characterized by bleeding symptoms similar to those in hemophilia or parahemophilia, that are caused by single deficiency of FV or FVIII, respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma levels of coagulation factors V and VIII are in the range of 5 to 30% of normal.^[1]

Function

LMAN1_HUMAN Mannose-specific lectin. May recognize sugar residues of glycoproteins, glycolipids, or glycosylphosphatidyl inositol anchors and may be involved in the sorting or recycling of proteins, lipids, or both. The LMAN1-MCFD2 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.^[2] ^[3]

Publication Abstract from PubMed

ERGIC-53 transports certain subsets of newly synthesized secretory proteins and membrane proteins from the endoplasmic reticulum to the Golgi apparatus. Despite numerous structural and functional studies since its identification, the overall architecture and mechanism of action of ERGIC-53 remain unclear. Here we present cryo-EM structures of full-length ERGIC-53 in complex with its functional partner MCFD2. These structures reveal that ERGIC-53 exists as a homotetramer, not a homohexamer as previously suggested, and comprises a four-leaf clover-like head and a long stalk composed of three sets of four-helix coiled-coil followed by a transmembrane domain. 3D variability analysis visualizes the flexible motion of the long stalk and local plasticity of the head region. Notably, MCFD2 is shown to possess a Zn(2+)-binding site in its N-terminal lid, which appears to modulate cargo binding. Altogether, distinct mechanisms of cargo capture and release by ERGIC- 53 via the stalk bending and metal binding are proposed.

Structure of full-length ERGIC-53 in complex with MCFD2 for cargo transport.,Watanabe S, Kise Y, Yonezawa K, Inoue M, Shimizu N, Nureki O, Inaba K Nat Commun. 2024 Mar 16;15(1):2404. doi: 10.1038/s41467-024-46747-1. PMID:38493152^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nichols WC, Terry VH, Wheatley MA, Yang A, Zivelin A, Ciavarella N, Stefanile C, Matsushita T, Saito H, de Bosch NB, Ruiz-Saez A, Torres A, Thompson AR, Feinstein DI, White GC, Negrier C, Vinciguerra C, Aktan M, Kaufman RJ, Ginsburg D, Seligsohn U. ERGIC-53 gene structure and mutation analysis in 19 combined factors V and VIII deficiency families. Blood. 1999 Apr 1;93(7):2261-6. PMID:10090935
↑ Nufer O, Kappeler F, Guldbrandsen S, Hauri HP. ER export of ERGIC-53 is controlled by cooperation of targeting determinants in all three of its domains. J Cell Sci. 2003 Nov 1;116(Pt 21):4429-40. Epub 2003 Sep 16. PMID:13130098 doi:10.1242/jcs.00759
↑ Zhang B, Cunningham MA, Nichols WC, Bernat JA, Seligsohn U, Pipe SW, McVey JH, Schulte-Overberg U, de Bosch NB, Ruiz-Saez A, White GC, Tuddenham EG, Kaufman RJ, Ginsburg D. Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex. Nat Genet. 2003 Jun;34(2):220-5. PMID:12717434 doi:10.1038/ng1153
↑ Watanabe S, Kise Y, Yonezawa K, Inoue M, Shimizu N, Nureki O, Inaba K. Structure of full-length ERGIC-53 in complex with MCFD2 for cargo transport. Nat Commun. 2024 Mar 16;15(1):2404. PMID:38493152 doi:10.1038/s41467-024-46747-1