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

doi:10.1093/emboj/19.2.187

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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 internalizationand downregulation. We have investigated whether ubiquitylationalters a receptor cytoplasmic tail to reveal a previously maskedinternalization signal, or whether ubiquitin itself carries aninternalization signal. Using an $alpha$ -factor receptor-ubiquitin chimericprotein, we demonstrate that monoubiquitin can mediate internalizationof an activated receptor that lacks all cytoplasmic tail sequences.Furthermore, fusion of ubiquitin in-frame to the stable plasmamembrane protein Pma1p stimulates endocytosis of this protein.Ubiquitin does not carry a functional tyrosine- or di-leucine-basedinternalization signal. Instead, the three-dimensional structureof the folded ubiquitin polypeptide carries an internalizationsignal that consists of two surface patches surrounding the criticalresidues Phe4 and Ile44. We conclude that ubiquitin functionsas a novel regulated internalization signal that can be appendedto a plasma membrane protein to trigger downregulation.