All chapters


Disulfide Bonds in Protein Folding and Stability

Disulfide bonds are unique among post-translational modifications, as they add covalent crosslinks to the polypeptide chain. Accordingly, they can exert pronounced effects on protein folding and stability. This is of particular importance for secreted or cell surface proteins, where disulfide bonds are abundant and serve to stabilize proteins against unfolding and dissociation in the extracellular milieu. However, in addition to these bonds providing security to a natively folded protein or aiding the folding process by stabilizing folding intermediates, the cysteines that form these bonds can be perilous during the maturation of nascent polypeptide chains as they enter the endoplasmic reticulum where the concentration of unfolded proteins approaches millimolar levels. This danger is even greater if the native bonds ultimately form between non-consecutive cysteines that are distant in the linear sequence or if non-native bonds are a prerequisite to achieving the final, functional structure of a protein. A wealth of exquisite detail has been obtained from in vitro studies on the biophysical effects of disulfide bonds on protein folding. Correspondingly, in-depth in vivo studies have established that the same principles apply to oxidative folding in a cell, but reveal a much more complex folding trajectory for many of the proteins that have been examined. In this chapter, we review the biophysical properties of disulfide bonds and how they affect the structure and folding of individual proteins. Based on this, we discuss similarities and differences between in vitro and in vivo folding reactions. The types of disulfide bonds that form during co-translational protein folding are described, as are the cellular strategies for accommodating this risk-laden covalent modification. We conclude with a discussion of the impact of disulfide bonds on protein misfolding and human disease.

Publication details

Print publication date
31 Jul 2018
Copyright year
Print ISBN
ePub eISBN

From the book series:
Chemical Biology