8jp4
From Proteopedia
Cryo-EM structure of the head region of full-length ERGIC-53 with MCFD2 (form A)
Structural highlights
DiseaseLMAN1_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] FunctionLMAN1_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 PubMedERGIC-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
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