PEST sequences

MacKichan, M.L., Logeat, F., and Israel, A. (1996). Phosphorylation of pl05 PEST sequence via a redox insensitive pathway up-regulates processing of p50 NF-kB. J. Biol. Chem. 271, 6084- 6091. 

The phosphoprotein-ubiquitin ligases hgate ubiquitin exclusively to phosphorylated proteins. In this system, ubiquitination and degradation are controlled by the phosphorylation status of the target proteins, which is in turn dependent on the regulated activity of protein kinases (or protein phosphatases). Phosphorylation of the target proteins often occurs in sequence elements rich in the aminoacids P,E,S, and T (PEST sequences). For target proteins and the subunit structure, see 13.3.1. 

Cyclins D and E in mammals are short-hved proteins with a lifetime of only ca. 20 min. Their instability is due to the occurrence of certain sequences in the C-terminal region deletion of these sequences is associated with stabilization of the cyclins (see 13.3.1). These sequence elements are known as PEST sequences, based on their composition. Due to the short half-life, the D type cyclins require a constant stimulus at the transcription level to achieve the concentration in Gi phase necessary for activation of CDK4/6 and to initiate crossing of the restriction point. 

Substrate proteins are selected for Ub hgation based on a C-terminal target sequence. These sequences which, due to the occurrence of common amino acids, are known as PEST sequences, are targets for phosphorylation. In the phosphorylated form, they are recognized by the ubiquitin hgase complex and marked for degradation. 

The PEST search can be conducted at http //www.icnet.uk/LRITu/projects/pest/ runpest.html. Paste the query sequence, enter options, and click Submit button. Candidate PEST sequences with hydrophobicity index and PEST score are returned. 

Another nonlysosomal protein degradative system is dependent on calcium ions. They combine with specific protein residues in close proximity to each other proline, glutamate, serine, and threonine (PEST sequences). It is believed that a calcium-requiring proteinase (a metalloenzyme) recognizes the calcium and combines with it, thus achieving an active status, and then hydrolyzes the protein in the vicinity of the PEST sequence. 

Rechsteiner M, Rogers SW. 1996. PEST sequences and regulation by proteoloysis. Trends Biochem Sci 21 267-271. 

Peptide motifs. Proteins with certain homologous sequences are rapidly degraded. For example, proteins that have extended sequences containing proline, glutamate, serine, and threonine have half-lives of less than 2 hours. (PEST sequences are named for the one-letter abbreviations for these amino acids. See Table 5.1.) The cyclin destruction box is a set of homologous nine-residue sequences near the N-terminus of cyclins that ensures rapid ubiquination. 

Another signal for protein degradation, independent of ubiquitination, is the presence of PEST sequences, which are amino-acid sequences containing large amounts of Pro (P), Glu (E), Ser (S), and Thr (T). The presence of multiple PEST sequences is correlated with high turnover rates of proteins. Experiments have shown that, for some proteins, removal of the PEST sequences can result in protein stabilization. However, the mechanism by which PEST sequences determine protein turnover rates is still not known, although it is thought to be mediated by sequence-selective proteases. 

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