Surface hydrophobicity and intracellular degradation of proteins.

Cellular proteins turn over with rates varying more than 1000 fold and all organelles are involved in this process of renewal. Although the surface of protein molecules bears many peptide bonds, which could be potential cleavage sites for proteases, only a small fraction of all cellular proteins is subject to very rapid turnover, with half-lives of less than one hour in mammalian cells. Many of these proteins play key roles in basic regulatory mechanisms. One of the features that make proteins short-lived is surface hydrophobicity which is increased in nascent polypeptide chains before association with chaperones, in oligomeric proteins before the association of the monomers, and in many enzymes in absence of their substrates. Cellular proteases tend to act most rapidly on peptide bonds involving (or near to) apolar amino acids. A striking correlation has been found between the half-lives of cellular proteins and their surface hydrophobicity. Clusters of hydrophobic residues appear to be necessary for ubiquitination. Apolar amino acid residues that are hidden can be exposed after oxidation of proteins or after binding of ubiquitin molecules. Additionally, tetraubiquitin exposes many hydrophobic residues which are essential for targeting of the ubiquitinated substrate proteins to a 50 kDa-subunit of the 26S-protease.