4gky | pdb_00004gky
Crystal structure of a carbohydrate-binding domain
Structural highlights
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 PubMedLMAN1 (ERGIC-53) is a key mammalian cargo receptor responsible for the export of a subset of glycoproteins from the endoplasmic reticulum. Together with its soluble coreceptor MCFD2, LMAN1 transports coagulation factors V (FV) and VIII (FVIII). Mutations in LMAN1 or MCFD2 cause the genetic bleeding disorder combined deficiency of FV and FVIII (F5F8D). The LMAN1 carbohydrate recognition domain (CRD) binds to both glycoprotein cargo and to MCFD2 in a Ca2+-dependent manner. To understand the biochemical basis and regulation of LMAN1 binding to glycoprotein cargo, we solved crystal structures of the LMAN1-CRD bound to Man-alpha-1,2-Man, the terminal carbohydrate moiety of high-mannose glycans. Our structural data, combined with mutagenesis and in vitro binding assays, define the central mannose binding site on LMAN1 and pinpoint histidine 178 and glycines 251/252 as critical residues for FV/FVIII binding. We also show that mannobiose binding is relatively independent of pH in the range relevant for ER-to-Golgi traffic, but is sensitive to lowered Ca2+ concentrations. The distinct LMAN1-MCFD2 interaction is maintained at these lowered Ca2+ concentrations. Our results suggest that compartmental changes in Ca2+ concentration regulate glycoprotein cargo binding and release from the LMAN1-MCFD2 complex in the early secretory pathway. Structural characterization of carbohydrate binding by LMAN1 provides new insight into the endoplasmic reticulum export of FV and FVIII.,Zheng C, Page RC, Das V, Nix JC, Wigren E, Misra S, Zhang B J Biol Chem. 2013 May 24. PMID:23709226[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||||
