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Molecular and Cellular Biology, March 2003, p. 1546-1557, Vol. 23, No. 5
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.5.1546-1557.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The C Terminus of Initiation Factor 4E-Binding Protein 1 Contains Multiple Regulatory Features That Influence Its Function and Phosphorylation

Xuemin Wang, Wei Li, Josep-Lluis Parra, Anne Beugnet, and Christopher G. Proud*

Division of Molecular Physiology, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom,

Received 30 August 2002/ Returned for modification 22 October 2002/ Accepted 6 December 2002

Eukaryotic initiation factor 4E (eIF4E) binds the mRNA cap structure and forms eIF4F complexes that recruit 40S subunits to the mRNA. Formation of eIF4F is blocked by eIF4E-binding proteins such as 4E-BP1, which interacts with eIF4E via a motif in the center of its 118-residue sequence. 4E-BP1 plays key roles in cell proliferation, growth, and survival. Binding of 4E-BP1 to eIF4E is regulated by hierarchical multisite phosphorylation. Here we demonstrate that three different features in the C terminus of 4E-BP1 play distinct roles in regulating its phosphorylation and function. Firstly, we identify a new phosphorylation site in its C terminus (S101). A serine or glutamate at this position is required for efficient phosphorylation at Ser65. A second C-terminal site, S112, directly affects binding of 4E-BP1 to eIF4E without influencing phosphorylation of other sites. Thirdly, a conserved C-terminal motif influences phosphorylation of multiple residues, including rapamycin-insensitive sites. These relatively long-range effects are surprising given the reportedly unstructured nature of 4E-BP1 and may imply that phosphorylation of 4E-BP1 and/or binding to eIF4E induces a more-ordered structure. 4E-BP2 and -3 lack phosphorylatable residues corresponding to both S101 and S112. However, in 4E-BP3, replacement of the alanine at the position corresponding to S112 by serine or glutamate did not confer the ability to be released from eIF4E in response to insulin.

* Corresponding author. Mailing address: Division of Molecular Physiology, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom. Phone: 44 1382 344919. Fax: 44 1382 322424. E-mail: c.g.proud{at}dundee.ac.uk.

Molecular and Cellular Biology, March 2003, p. 1546-1557, Vol. 23, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.5.1546-1557.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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