Protein damage can be divided into two major classes: conformational and covalent¹. As shown in the diagram below, conformational damage refers to unfolding of the protein--loss of the three-dimensional shape that is essential to the normal function of any protein. Conformational damage can result from heating, attack by free radicals, chemicals, pH changes, etc. Covalent damage is a chemical change in the amino acids that make up the protein, such as oxidation, isomerization or formation of isoaspartate (more on the next page). Many of these changes can occur spontaneously or can be induced or accelerated by environmental factors. Both kinds of damage can drastically affect protein function.

Repair of protein damage depends on (i) the ability to recognize a change in a protein as abnormal, and (ii) a means of reversing the change. The best-known protein-repair mechanisms are the well-studied chaperone systems for refolding conformationally damaged proteins². Detecting covalent damage is more difficult, but several covalent repair systems have been identified, including methionine sulfoxide reductase³, peptidyl-prolyl isomerases⁴ and the L-isoaspartyl protein carboxyl methyltransferase (or PCM), which repairs isoaspartate and is discussed in detail on the following pages. Proteins that cannot be repaired are eventually degraded and recycled.

Why repair proteins? Certainly, repairing any damage to DNA is critical--and many DNA repair systems are well-known. Proteins, however, seem dispensable at first glance: as long as its DNA is intact, a cell can synthesize new copies of proteins indefinitely. But what happens when protein synthesis is limited? For example, human red blood cells lack nuclei yet must function in circulation for 120 days without making new proteins. Nutrient-limited bacteria drastically reduce metabolism, including translation of proteins. The crystallin proteins in the lens of the eye are never replaced during an individiual's lifetime. And any cell which is not rapidly growing and dividing becomes more dependent on its existing proteins. Protein synthesis is "expensive" to a cell, and repair can be a cost-effective alternative to replacement when damage can be readily recognized.

Next: isoaspartyl formation >>

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¹Reviewed in: Visick, J. E., and S. Clarke. 1995. Repair, refold, recycle: how bacteria can deal with spontaneous and environmental damage to proteins. Mol. Microbiol. 16:835-845.

²Reviewed in: Bukau, B., and A. L. Horwich. 1998. The Hsp70 and Hsp60 chaperone machines. Cell 92:351-366.

³Reviewed in: Stadtman, E. R., J. Moskovitz, B. S. Berlett, and R. L. Levine. 2002. Cyclic oxidation and reduction of protein methionine residues is an important antioxidant mechanism. Mol. Cell. Biochem. 234-235:3-9.

⁴Reviewed in: Gothel, S. F., and M. A. Marahiel. 1999. Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell. Mol. Life Sci. 55:423-36.