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© The Rockefeller University Press, 0021-9525/2002/7/10-b $5.00
The Journal of Cell Biology, Volume 158, Number 1, July 8, 2002 10-b-10

Stable globin needs a partner

Without AHSP, globin inclusion bodies (purple) form. Weiss/Macmillan

In the absence of a binding partner, such as when ß-globin is mutated in ß-thalassemia, the unstable -globin protein tends to form toxic inclusion bodies. Molecular chaperones that stabilize hemoglobin have been proposed to exist, but have not been found, until now. Anthony Kihm, Mitchell Weiss, and colleagues (University of Pennsylvania, Philadelphia, PA) have now identified a protein that protects -globin until it can find ß-globin and form hemoglobin A (HbA).

This chaperone-like protein, AHSP, was identified in a screen for genes induced by the transcription factor GATA-1, which promotes erythrocyte differentiation. Many genes were induced by GATA-1, but Weiss found AHSP particularly interesting because it was strongly and specifically expressed in RBCs and had no known function. Screens for protein–protein interactions revealed that AHSP bound to -globin, but not to ß-globin or HbA.

AHSP prevented -globin precipitation in cells and in vitro. In mice lacking AHSP, erythrocytes contained inclusion bodies and turned over more rapidly than in wild-type mice. "The phenotype of the knock-out mice was relatively mild, probably because red cells do a good job of balancing the amount of - and ß-globin they produce," says Weiss. "So, AHSP is not absolutely essential when things are good, but may become more important when things aren't going so well."

Thus, AHSP could be a genetic modifier of ß-thalassemia. Patients with this disease suffer twofold from a lack of ß-globin—they are unable to make enough HbA for good respiratory capacity, and they have an excess of toxic, free -globin. If a drug could be made to mimic AHSP, it might help offset free -globin toxicity. This could decrease transfusion requirements in some patients.

Reference:

Kihm, A.J., et al. 2002. Nature. 417:758–763.[CrossRef][Medline]

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 223K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                            What's this?