Why Does it Use ATP?

How does the cell know which proteins to degrade, and when?

The other notable feature of intracellular proteolysis is its requirement for cellular energy. Since proteolysis is an exergonic reaction, the only reason to use energy is to control specificity (i.e., which proteins get degraded, when and where.)

The energy of ATP is utilized in two ways:

  • to maintain a separate compartment containing the proteolytic enzymes.
  • to deliver the substrate proteins to that compartment for degradation.
atpdep

 

Catabolism of intracellular protein: molecular aspects. Beynon RJ; Bond JS . Am J Physiol 251: C141-52 (1986).


The lysosome must maintain an acidic pH for the action of it's proteases. Substrates are selected by either a non-specific pathway (microautophagy), or selective uptake of proteins containing a specific peptide sequence (KFERQ) by a 70 kilodalton heat-shock protein.

 Selective binding and uptake of ribonuclease A and glyceraldehyde-3-phosphate dehydrogenase by isolated rat liver lysosomes. Cuervo AM; Terlecky SR; Dice JF; Knecht E. J Biol Chem 269: 26374-80 (1994).


The endoplamic reticulum is the site of degradation of misfolded secretory proteins and excess subunits of cell surface receptors. The integrety of this compartment and the activity of the proteases can be influenced by energy levels and redox potential.

 Regulation of selective protein degradation in the endoplasmic reticulum by redox potential. Young J; Kane LP; Exley M; Wileman T. J Biol Chem 268: 19810-8 (1993).


The soluble ubiquitin-dependent system sequesters it proteases in a 26S proteasome particle. Substrates are selected by specific covalent modification (ubiquitinylation) and subsequent binding to the proteasome. Some ubiquitinylated proteins can apparently be degraded in the lysosome, but this may be via microautophaghy.

The ubiquitin-mediated proteolytic pathway: mechanisms of recognition of the proteolytic substrate and involvement in the degradation of native cellular proteins. Ciechanover A; Schwartz AL. FASEB J 8: 182-91 (1994).