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Molecular and Cellular Biology, July 1999, p. 4572-4581, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Assembly of the alpha -Globin mRNA Stability Complex Reflects Binary Interaction between the Pyrimidine-Rich 3' Untranslated Region Determinant and Poly(C) Binding Protein alpha CP

Alexander N. Chkheidze, Dmitry L. Lyakhov, Alexander V. Makeyev, Julia Morales,dagger Jian Kong, and Stephen A. Liebhaber*

Howard Hughes Medical Institute and Departments of Genetics and Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Received 9 November 1998/Returned for modification 17 December 1998/Accepted 30 March 1999

Globin mRNAs accumulate to 95% of total cellular mRNA during terminal erythroid differentiation, reflecting their extraordinary stability. The stability of human alpha -globin mRNA is paralleled by formation of a sequence-specific RNA-protein (RNP) complex at a pyrimidine-rich site within its 3' untranslated region (3'UTR), the alpha -complex. The proteins of the alpha -complex are widely expressed. The alpha -complex or a closely related complex also assembles at pyrimidine-rich 3'UTR segments of other stable mRNAs. These data suggest that the alpha -complex may constitute a general determinant of mRNA stability. One or more alpha CPs, members of a family of hnRNP K-homology domain poly(C) binding proteins, are essential constituents of the alpha -complex. The ability of alpha CPs to homodimerize and their reported association with additional RNA binding proteins such as AU-rich binding factor 1 (AUF1) and hnRNP K have suggested that the alpha -complex is a multisubunit structure. In the present study, we have addressed the composition of the alpha -complex. An RNA titration recruitment assay revealed that alpha CPs were quantitatively incorporated into the alpha -complex in the absence of associated AUF1 and hnRNP K. A high-affinity direct interaction between each of the three major alpha CP isoforms and the alpha -globin 3'UTR was detected, suggesting that each of these proteins might be sufficient for alpha -complex assembly. This sufficiency was further supported by the sequence-specific binding of recombinant alpha CPs to a spectrum of RNA targets. Finally, density sedimentation analysis demonstrated that the alpha -complex could accommodate only a single alpha CP. These data established that a single alpha CP molecule binds directly to the alpha -globin 3'UTR, resulting in a simple binary structure for the alpha -complex.

* Corresponding author. Mailing address: Room 428 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-7834. Fax: (215) 898-1257. E-mail: Liebhaber{at}mail.med.upenn.edu.

dagger Present address: CNRS UPR 9042, 29680 Roscoff, France.

Molecular and Cellular Biology, July 1999, p. 4572-4581, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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