title: An abundant erythroid protein that stabilizes free alpha-haemoglobin.
abstract: The development of red blood cells (erythrocytes) is distinguished by high-level production of the oxygen carrier, haemoglobin A (HbA), a heterotetramer of alpha- and beta-haemoglobin subunits. HbA synthesis is coordinated to minimize the accumulation of free subunits that form cytotoxic precipitates. Molecular chaperones that regulate globin subunit stability, folding or assembly have been proposed to exist but have never been identified. Here we identify a protein stabilizing free alpha-haemoglobin by using a screen for genes induced by the essential erythroid transcription factor GATA-1 (refs 4, 5). Alpha Haemoglobin Stabilizing Protein (AHSP) is an abundant, erythroid-specific protein that forms a stable complex with free alpha-haemoglobin but not with beta-haemoglobin or haemoglobin A (alpha(2)beta(2)). Moreover, AHSP specifically protects free alpha-haemoglobin from precipitation in solution and in live cells. AHSP-gene-ablated mice exhibit reticulocytosis and abnormal erythrocyte morphology with intracellular inclusion bodies that stain positively for denatured haemoglobins. Hence, AHSP is required for normal erythropoiesis, probably acting to block the deleterious effects of free alpha-haemoglobin precipitation. Accordingly, AHSP gene dosage is predicted to modulate pathological states of alpha-haemoglobin excess, such as beta-thalassaemia.
authors.affiliation: The Children's Hospital of Philadelphia, Division of Hematology and the University of Pennsylvania, Philadelphia, Pennsylvania 19104-616, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kihm
authors.forename: Yi
authors.initials: Y
authors.lastname: Kong
authors.forename: Wei
authors.initials: W
authors.lastname: Hong
authors.forename: J Eric
authors.initials: JE
authors.lastname: Russell
authors.forename: Susan
authors.initials: S
authors.lastname: Rouda
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Adachi
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Blobel
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D011232:Chemical Precipitation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006454:Hemoglobins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D012996:Solutions; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism; D017086:beta-Thalassemia / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; D006454:Hemoglobins; D018832:Molecular Chaperones; D016877:Oxidants; D012996:Solutions; D014157:Transcription Factors