title: An erythroid chaperone that facilitates folding of alpha-globin subunits for hemoglobin synthesis.
abstract: Erythrocyte precursors produce abundant alpha- and beta-globin proteins, which assemble with each other to form hemoglobin A (HbA), the major blood oxygen carrier. alphaHb-stabilizing protein (AHSP) binds free alpha subunits reversibly to maintain their structure and limit their ability to generate reactive oxygen species. Accordingly, loss of AHSP aggravates the toxicity of excessive free alpha-globin caused by beta-globin gene disruption in mice. Surprisingly, we found that AHSP also has important functions when free alpha-globin is limited. Thus, compound mutants lacking both Ahsp and 1 of 4 alpha-globin genes (genotype Ahsp(-/-)alpha-globin*(alpha/alphaalpha)) exhibited more severe anemia and Hb instability than mice with either mutation alone. In vitro, recombinant AHSP promoted folding of newly translated alpha-globin, enhanced its refolding after denaturation, and facilitated its incorporation into HbA. Moreover, in erythroid precursors, newly formed free alpha-globin was destabilized by loss of AHSP. Therefore, in addition to its previously defined role in detoxification of excess alpha-globin, AHSP also acts as a molecular chaperone to stabilize nascent alpha-globin for HbA assembly. Our findings illustrate what we believe to be a novel adaptive mechanism by which a specialized cell coordinates high-level production of a multisubunit protein and protects against various synthetic imbalances.
authors.affiliation: Cell and Molecular Biology Graduate Program, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yu
authors.forename: Yi
authors.initials: Y
authors.lastname: Kong
authors.forename: Louis C
authors.initials: LC
authors.lastname: Dore
authors.forename: Osheiza
authors.initials: O
authors.lastname: Abdulmalik
authors.forename: Anne M
authors.initials: AM
authors.lastname: Katein
authors.forename: Suiping
authors.initials: S
authors.lastname: Zhou
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.forename: David
authors.initials: D
authors.lastname: Gell
authors.forename: Joel P
authors.initials: JP
authors.lastname: Mackay
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gow
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001059:Apoproteins / Q000378:metabolism; D001798:Blood Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D048430:Cell Shape; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism*; D006454:Hemoglobins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D017510:Protein Folding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012156:Reticulocytes / Q000378:metabolism
chemical_list: C511177:Ahsp protein, mouse; D001059:Apoproteins; D001798:Blood Proteins; D006454:Hemoglobins; D018832:Molecular Chaperones; D021122:Protein Subunits