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Disabling the folding catalyst is the last critical step in α‐lytic protease folding
Author(s) -
Cunningham Erin L.,
Agard David A.
Publication year - 2004
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.03389704
Subject(s) - foldase , chemistry , protease , biophysics , protein folding , cleavage (geology) , proteases , folding (dsp implementation) , native state , stereochemistry , crystallography , biochemistry , enzyme , biology , groel , paleontology , escherichia coli , fracture (geology) , electrical engineering , gene , engineering
Alpha‐Lytic protease (αLP) is an extracellular bacterial pro‐protease marked by extraordinary conformational rigidity and a highly cooperative barrier to unfolding. Although these properties successfully limit its proteolytic destruction, thereby extending the functional lifetime of the protease, they come at the expense of foldability (t 1/2 = 1800 yr) and thermodynamic stability (native αLP is less stable than the unfolded species). Efficient folding has required the coevolution of a large N‐terminal pro region (Pro) that rapidly catalyzes αLP folding (t 1/2 = 23 sec) and shifts the thermodynamic equilibrium in favor of folded protease through tight native‐state binding. Release of active αLP from this stabilizing, but strongly inhibitory, complex requires the proteolytic destruction of Pro. αLP is capable of initiating Pro degradation via cleavage of a flexible loop within the Pro C‐terminal domain. This single cleavage event abolishes Pro catalysis while maintaining strong native‐state binding. Thus, the loop acts as an Achilles' heel by which the Pro foldase machinery can be safely dismantled, preventing Pro‐catalyzed unfolding, without compromising αLP native‐state stability. Once the loop is cleaved, Pro is rapidly degraded, releasing active αLP.