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19 (2): 187-198

Copyright © 2000 by the European Molecular Biology Organization.

The EMBO Journal Vol. 19,pp. 187-198, 2000, Copyright © European Molecular Biology Organization

Monoubiquitin carries a novel internalization signal that is appended to activated receptors

Susan C. Shih, Katherine E. Sloper-Mould and Linda Hicke

Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, IL 60208, USA
1   Corresponding author
   e-mail: l-hicke{at}nwu.edu
   S.C.Shih and K.E.Sloper-Mould contributed equally to this work

Ubiquitin modification of signal transducing receptors at the plasma membrane is necessary for rapid receptor internalization and downregulation. We have investigated whether ubiquitylation alters a receptor cytoplasmic tail to reveal a previously masked internalization signal, or whether ubiquitin itself carries an internalization signal. Using an alpha -factor receptor-ubiquitin chimeric protein, we demonstrate that monoubiquitin can mediate internalization of an activated receptor that lacks all cytoplasmic tail sequences. Furthermore, fusion of ubiquitin in-frame to the stable plasma membrane protein Pma1p stimulates endocytosis of this protein. Ubiquitin does not carry a functional tyrosine- or di-leucine-based internalization signal. Instead, the three-dimensional structure of the folded ubiquitin polypeptide carries an internalization signal that consists of two surface patches surrounding the critical residues Phe4 and Ile44. We conclude that ubiquitin functions as a novel regulated internalization signal that can be appended to a plasma membrane protein to trigger downregulation.

Keywords: endocytosis/internalization signal/protein targeting/receptor downregulation/ubiquitin

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