TY - JOUR
T1 - Aeropin from the extremophile pyrobaculum aerophilum bypasses the serpin misfolding trap
AU - Cabrita, Lisa
AU - Irving, James Alexander
AU - Pearce, Mary Catherine
AU - Whisstock, James
AU - Bottomley, Stephen Paul
PY - 2007
Y1 - 2007
N2 - Serpins are metastable proteinase inhibitors. Serpin metastability drives both a large conformational change that is utilized during proteinase inhibition, and confers an inherent structural flexibility that renders serpins susceptible to aggregation under certain conditions. These include point mutations - the basis of a number of important human genetic diseases - small changes in pH, and an increase in temperature. Many studies of serpins from mesophilic organisms have highlighted an inverse relationship: mutations that confer a marked increase in serpin stability compromise inhibitory activity. Here we present the first biophysical characterisation of a metastable serpin from a hyperthermophilic organism. Aeropin, from the archaeon Pyrobaculum aerophilum, is both highly stable and an efficient proteinase inhibitor. We also demonstrate that due to high kinetic barriers, aeropin does not readily form the partially unfolded precursor to serpin aggregation. We conclude that stability and activity are not mutually exclusive properties in the context of the serpin fold, and propose that the increased stability of aeropin is due to an unfolding pathway which minimises the formation of an aggregation-prone intermediate ensemble, thereby enabling aeropin to bypass the misfolding fate observed with other serpins.
AB - Serpins are metastable proteinase inhibitors. Serpin metastability drives both a large conformational change that is utilized during proteinase inhibition, and confers an inherent structural flexibility that renders serpins susceptible to aggregation under certain conditions. These include point mutations - the basis of a number of important human genetic diseases - small changes in pH, and an increase in temperature. Many studies of serpins from mesophilic organisms have highlighted an inverse relationship: mutations that confer a marked increase in serpin stability compromise inhibitory activity. Here we present the first biophysical characterisation of a metastable serpin from a hyperthermophilic organism. Aeropin, from the archaeon Pyrobaculum aerophilum, is both highly stable and an efficient proteinase inhibitor. We also demonstrate that due to high kinetic barriers, aeropin does not readily form the partially unfolded precursor to serpin aggregation. We conclude that stability and activity are not mutually exclusive properties in the context of the serpin fold, and propose that the increased stability of aeropin is due to an unfolding pathway which minimises the formation of an aggregation-prone intermediate ensemble, thereby enabling aeropin to bypass the misfolding fate observed with other serpins.
UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17635906
M3 - Article
SN - 0021-9258
VL - 282
SP - 26802
EP - 26809
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -