The degradation is critical to activation and inactivation of regulatory
proteins involved in signaling pathways to cell growth, differentiation, stress responses
and cell death programs. Proteins carry domains and sequence motifs that function as
prerequisite for their proteolysis by either individual proteases or the 26S multicomplex
proteasomes. Two models for entry of substrates into the proteasomes have been
considered. In one model, it is proposed that the ubiquitin chain attached to the protein
serves as recognition element to drag them into the 19S regulatory particle, which
promotes the unfolding required to its access into the 20S catalytic chamber. In second
model, it is proposed that an unstructured tail located at amino or carboxyl terminus
directly track proteins into the 26S/20S proteasomes. Caspases are cysteinyl aspartate
proteases that control diverse signaling pathways, promoting the cleavage at one or two
sites of hundreds of structural and regulatory protein substrates. Caspase cleavage sites
are commonly found within PEST motifs, which are segments rich in proline (P),
glutamic acid (D), aspartic acid (E) and serine (S) or threonine (T) residues.
Considering that N- and C- terminal peptide carrying PEST motifs form disordered
loops in the globular proteins after caspase cleavage. These exposed termini serve as
unstructured initiation site or degron that target specific caspase substrates to the
ubiquitin-proteasome system. Here we analyzed this hypothesis based on a list of
caspase substrate proteins containing PEST motif.
Proteasome, caspases, protein degradation, protein structure,
Intrinsically unstructured proteins, peptides, N-end-rule, PEST motif, apoptosis,
necrosis, inflammation, cancer, cell cycle, DNA repair, differentiation
University of São Paulo, Department of Pharmacology, Institute of Biomedical Sciences, Av Lineu Prestes 1524 CEP 05508-900 São Paulo SP.