Tuesday, June 05, 2007

Protein Turnover

One might assume that only growing or reproducing cells would require new protein molecules—and therefore a supply of amino acids—but this is not the case. Proteins are continually synthesized and degraded in all cells, a process called turnover. Individual proteins turn over at different rates. Their half-lives can vary from a few minutes to several weeks but the half-life of a given protein in different organs and species is generally similar. Rapid protein turnover ensures that some regulatory proteins are degraded so that the cell can respond to constantly changing conditions. Such proteins have evolved to be relatively unstable. The rate of hydrolysis of a protein can be inversely related to the stability of its tertiary structure—misfolded and unfolded proteins are quickly degraded.

In eukaryotic cells, some proteins are degraded to amino acids in the lysosomes. In these cases, vesicles containing material to be destroyed fuse with lysosomes, and various lysosomal proteases hydrolyze the engulfed proteins. The lysosomal enzymes have broad substrate specificities, so all the trapped proteins are extensively degraded.

Some proteins have very short half-lives because they are specifically targeted for degradation. Abnormal proteins are also selectively hydrolyzed. The pathway for the selective hydrolysis of these proteins in eukaryotic cells requires the protein ubiquitin. Ubiquitin is Monday's Molecule #29. It is a small, highly conserved protein of about 76 amino acid residues.

Side-chain amino groups of lysine residues in the target protein are covalently linked to the C-terminus of ubiquitin in a complex pathway that involves ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3). This pathway is coupled to ATP hydrolysis—one ATP molecule is hydroylzed for every ubiquitin molecule attached to the target protein. The ubiquitinated protein is hydrolyzed to peptides by the action of a large multiprotein complex called the proteasome (or proteosome). This process occurs in both the cytosol and the nucleus.

Other proteases catalyze hydrolysis of the resulting peptides. ATP is required to assemble the proteasome and to hydrolyze the ubiquitinated protein. Before this pathway was discovered there was no explanation for the surprising observation that the degradation of many proteins requires ATP.

Adapted from Horton et al. Principles of Biochemistry 4th edition
©Laurence A. Moran and Pearson/Prentice Hall


  1. Proteases only hydrolyze peptides when the equilibrium favors it. Under conditions of dehydration, the equilibrium favors the making of peptides.

    As the lysosome shrinks, does it ever get sufficiently dehydrated that proteases might run in the other direction and make peptides out of amino acids? The lysosome is highly enriched with cysteine, and cysteine proteases.

    Might this be a way that proteases could "self-assemble" and select for activity via diurnal cycles of hydration and dehydration in a pre-biotic Earth?

  2. I doubt proteasomes could ever act in reverse. The peptide hydrolysis is achieved via nucleophilic attack. And dehydrating the proteasome would change it's structure and probably eliminate any catalytic activity.

    However, theoretically it's possible that changing the structure (via dehydration) would result in a new active site that could form peptide bonds instead of break them, but that would be a coincidence for the record books...

  3. I doubt proteasomes could ever act in reverse.

    There are a number of papers demonstrating that proteasomes can in fact act in reverse; it seems to be, unsurprisingly, a rare event, but detectable in the context of MHC class I antigen presentation. See, for example,
    Science. 2006 Sep 8;313(5792):1444-7.
    Science. 2004 Apr 23;304(5670):587-90.

  4. What is the rate of protein turnover in (g/aa day)if breakdown is greater than synthesis, is it the difference of the two? or is it equal to synthesis? anyone?

  5. It should also be noted that proteosomal degradation requires that proteins to be degraded generally be poly-ubiquitinated, whereas mono-ubiquitination is used for signaling, activity modulation and subcellular localization etc. The specific lysine to which the (poly)ubiquitination is conjugated also makes a very large difference in subsequent downstream protein processing.