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- Title
An erythroid chaperone that facilitates folding of α-globin subunits for hemoglobin synthesis.
- Authors
Xiang Yu; Yi Kong; Dore, Louis C.; Abdulmalik, Osheiza; Katein, Anne M.; Suiping Zhou; Choi, John K.; Gell, David; Mackay, Joel P.; Gow, Andrew J.; Weiss, Mitchell J.
- Abstract
Erythrocyte precursors produce abundant α- and β-globin proteins, which assemble with each other to form hemoglobin A (HbA), the major blood oxygen carrier. αHb-stabilizing protein (AHSP) binds free α 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 α-globin caused by β-globin gene disruption in mice. Surprisingly, we found that AHSP also has important functions when free α-globin is limited. Thus, compound mutants lacking both Ahsp and 1 of 4 α-globin genes (genotype Ahsp-/-α-globin*α/αα) exhibited more severe anemia and Hb instability than mice with either mutation alone. In vitro, recombinant AHSP promoted folding of newly translated α-globin, enhanced its refolding after denaturation, and facilitated its incorporation into HbA. Moreover, in erythroid precursors, newly formed free α-globin was destabilized by loss of AHSP. Therefore, in addition to its previously defined role in detoxification of excess α-globin, AHSP also acts as a molecular chaperone to stabilize nascent α-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.
- Subjects
ERYTHROCYTES; GLOBIN; HEMOGLOBINS; DENATURATION of proteins; DETOXIFICATION (Alternative medicine)
- Publication
Journal of Clinical Investigation, 2007, Vol 117, p1856
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI31664