  Understanding protein folding has been one of the great challenges in
biochemistry and molecular biophysics. Over the past 50 years, many
thermodynamic and kinetic studies have been performed addressing the stability
of globular proteins. In comparison, advances in the membrane protein folding
field lag far behind. Although membrane proteins constitute about a third of
the proteins encoded in known genomes, stability studies on membrane proteins
have been impaired due to experimental limitations. Furthermore, no systematic
experimental strategies are available for folding these biomolecules in vitro.
Common denaturing agents such as chaotropes usually do not work on helical
membrane proteins, and ionic detergents have been successful denaturants only
in few cases. Refolding a membrane protein seems to be a craftsman work, which
is relatively straightforward for transmembrane {\beta}-barrel proteins but
challenging for {\alpha}-helical membrane proteins. Additional complexities
emerge in multidomain membrane proteins, data interpretation being one of the
most critical. In this review, we will describe some recent efforts in
understanding the folding mechanism of membrane proteins that have been
reversibly refolded allowing both thermodynamic and kinetic analysis. This
information will be discussed in the context of current paradigms in the
protein folding field.
