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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The N-glycosylated membrane domain of band 3 consists of multiple membrane spanning segments that come together to form a regulated transmembrane passage for the exchange of anions. In this article we review the structural features of the membrane domain of band 3. Electron microscopic analysis of 2-dimensional crystals have confirmed the dimeric nature of the protein and has provided the overall shape of the membrane domain. The high degree of sequence identity in the transmembrane segments, and the finding that these segments are helical and remain tightly associated after proteolytic cleavage of the connecting loops, suggests that the interactions between transmembrane helices are specific and form the foundation for the structure of the membrane domain. N-glycosylation of band 3 is not essential for the transport function of the protein. N-glycosylation mutagenesis indicates that band 3 can be glycosylated on multiple loops and spans the membrane 12 times. Red cell diseases (HEMPAS and SAO) that affect the band 3 oligosaccharide structure and other properties of the protein are the subject of continued studies.
Cell Mol Biol (Noisy-le-grand) 1996 Nov
PMID:Structure of the band 3 transmembrane domain. 896 Jul 79

The biosynthesis, structures, and functions of O-glycosylation, as a complex posttranslational event, is reviewed and compared for the various types of O-glycans. Mucin-type O-glycosylation is initiated by tissue-specific addition of a GalNAc-residue to a serine or a threonine of the fully folded protein. This event is dependent on the primary, secondary, and tertiary structure of the glycoprotein. Further elongation and termination by specific transferases is highly regulated. We also describe some of the physical and biological properties that O-glycosylation confers on the protein to which the sugars are attached. These include providing the basis for rigid conformations and for protein stability. Clustering of O-glycans in Ser/Thr(/Pro)-rich domains allows glycan determinants such as sialyl Lewis X to be presented as multivalent ligands, essential for functional recognition. An additional level of regulation, imposed by exon shuffling and alternative splicing of mRNA, results in the expression of proteins that differ only by the presence or absence of Ser/Thr(/Pro)-rich domains. These domains may serve as protease-resistant spacers in cell surface glycoproteins. Further biological roles for O-glycosylation discussed include the role of isolated mucin-type O-glycans in recognition events (e.g., during fertilization and in the immune response) and in the modulation of the activity of enzymes and signaling molecules. In some cases, the O-linked oligosaccharides are necessary for glycoprotein expression and processing. In contrast to the more common mucin-type O-glycosylation, some specific types of O-glycosylation, such as the O-linked attachment of fucose and glucose, are sequon dependent. The reversible attachment of O-linked GlcNAc to cytoplasmic and nuclear proteins is thought to play a regulatory role in protein function. The recent development of novel technologies for glycan analysis promises to yield new insights in the factors that determine site occupancy, structure-function relationship, and the contribution of O-linked sugars to physiological and pathological processes. These include diseases where one or more of the O-glycan processing enzymes are aberrantly regulated or deficient, such as HEMPAS and cancer.
Crit Rev Biochem Mol Biol 1998
PMID:Concepts and principles of O-linked glycosylation. 967 46

This review deals with several of the main autosomal recessive congenital disorders involving defective N-glycosylation of proteins (the addition of glycans linked to the polypeptide chain by a beta-linkage between the anomeric carbon of N-acetylglucosamine and the amido group of L-asparagine). These congenital disorders of glycosylation (CDG, previously known as carbohydrate-deficient glycoprotein syndromes) are a group of multisystemic diseases often involving severe psychomotor retardation. Six distinct variants of CDG in group I (types Ia-If) have been described to date and the defects have been localized to deficiencies in the assembly of the dolichylpyrophosphate-linked oligosaccharide N-glycan precursor and its transfer to asparagine residues on the nascent polypeptides. Two variants of CDG group II (types IIa and IIb) have been identified as defects in the processing of protein-bound N-glycans. Hereditary erythroblastic multinuclearity with a positive acidified-serum lysis test (HEMPAS; congenital dyserythropoietic anemia type II) presents as a relatively mild dyserythropoietic anemia. The genetic defect in most cases of HEMPAS is not known, but alpha-3/6-mannosidase II is involved in at least some patients. Leukocyte adhesion deficiency type II (LAD II) is a rare disorder characterized by recurrent infections, persistent leukocytosis and severe mental and growth retardation. LAD II is due to lack of availability of GDP-fucose. The study of these diseases and of relevant animal models has provided strong evidence that N-glycans are essential for normal mammalian development.
Cell Mol Life Sci 2001 Jul
PMID:Congenital disorders involving defective N-glycosylation of proteins. 1152 1

Congenital dyserythropoietic anemias (CDA) are genetic disorders characterized by anemia and ineffective erythropoiesis. Three main types of CDA have been distinguished: CDA I, CDAII and CDA III, whose loci have been already mapped. After the identification of the locus for CDA II, also known as HEMPAS (hereditary erythroblast multinuclearity with positive acidified serum test), on the long arm of chromosome 20 (20q11.2) we have analyzed by a mutational search seven candidate genes in a large series of CDA II patients. In particular, the following genes have been investigated: integrin beta 4 binding protein, ribophorin II, ubiquitin protein ligase ITCH, mannosil-oligosaccharide alpha-1,2-mannosidase like protein, erythrocyte protein band 4.1 like protein, zinc finger protein PLAGL2, and finally novel zinc finger protein. None of them resulted as the causative gene but several protein variants and DNA polymorphisms have been identified. These data exclude the role of the above mentioned genes in causing CDA II and add further information in the process of cloning the CDA II gene.
Blood Cells Mol Dis
PMID:Congenital dyserythropoietic anemia type II: exclusion of seven candidate genes. 1266 84

Congenital dyserythropoietic anemia type II, a recessive disorder of erythroid differentiation, is due to mutations in SEC23B, a component of the core trafficking machinery COPII. In no case homozygosity or compound heterozygosity for nonsense mutation(s) was found. This study represents the first description of molecular mechanisms underlying SEC23B hypomorphic genotypes by the analysis of five novel mutations. Our findings suggest that reduction of SEC23B gene expression is not associated with CDA II severe clinical presentation; conversely, the combination of a hypomorphic allele with one functionally altered results in more severe phenotypes. We propose a mechanism of compensation SEC23A-mediated which justifies these observations.
Blood Cells Mol Dis 2013 Jun
PMID:Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II. 2345 96

Congenital dyserythropoietic anemia type II (CDAII) is an autosomal recessive disease of ineffective erythropoiesis characterized by increased bi/multinucleated erythroid precursors in the bone marrow. CDAII results from mutations in SEC23B. The SEC23 protein is a core component of coat protein complex II-coated vesicles, which transport secretory proteins from the endoplasmic reticulum to the Golgi apparatus. Though the genetic defect underlying CDAII has been identified, the pathophysiology of this disease remains unknown. We previously reported that SEC23B-deficient mice die perinatally, exhibiting massive pancreatic degeneration, with this early mortality limiting evaluation of the adult hematopoietic compartment. We now report that mice with SEC23B deficiency restricted to the hematopoietic compartment survive normally and do not exhibit anemia or other CDAII characteristics. We also demonstrate that SEC23B-deficient hematopoietic stem cells (HSC) do not exhibit a disadvantage at reconstituting hematopoiesis when compared directly to wild-type HSC in a competitive repopulation assay. Secondary bone marrow transplants demonstrated continued equivalence of SEC23B-deficient and WT HSC in their hematopoietic reconstitution potential. The surprising discordance in phenotypes between SEC23B-deficient mice and humans may reflect an evolutionary shift in SEC23 paralog function and/or expression, or a change in a specific COPII cargo critical for erythropoiesis.
Mol Cell Biol 2014 Oct 01
PMID:Absence of a red blood cell phenotype in mice with hematopoietic deficiency of SEC23B. 2507 Nov 56

Congenital dyserythropoietic anemia type II (CDA II) is a hypo-productive anemia defined by ineffective erythropoiesis through maturation arrest of erythroid precursors. CDA II is an autosomal recessive disorder due to loss-of-function mutations in SEC23B. Currently, management of patients with CDA II is based on transfusions, splenectomy, or hematopoietic stem-cell transplantation. Several studies have highlighted benefits of ACE-011 (sotatercept) treatment of ineffective erythropoiesis, which acts as a ligand trap against growth differentiation factor (GDF)11. Herein, we show that GDF11 levels are increased in CDA II, which suggests sotatercept as a targeted therapy for treatment of these patients. Treatment of stable clones of SEC23B-silenced erythroleukemia K562 cells with the iron-containing porphyrin hemin plus GDF11 increased expression of pSMAD2 and reduced nuclear localization of the transcription factor GATA1, with subsequent reduced gene expression of erythroid differentiation markers. We demonstrate that treatment of these SEC23B-silenced K562 cells with RAP-011, a "murinized" ortholog of sotatercept, rescues the disease phenotype by restoring gene expression of erythroid markers through inhibition of the phosphorylated SMAD2 pathway. Our data also demonstrate the effect of RAP-011 treatment in reducing the expression of erythroferrone in vitro, thus suggesting a possible beneficial role of the use of sotatercept in the management of iron overload in patients with CDA II.
Int J Mol Sci 2020 Aug 04
PMID:RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway. 3275 40