Abstract
While the majority of proteins fold rapidly and spontaneously to their native states, the extracellular bacterial protease α-lytic protease (αLP) has a t 1/4 for folding of ~2,000 years, corresponding to a folding barrier of 30 kcal mol-1. αLP is synthesized as a pro-enzyme where its pro region (Pro) acts as a foldase to stabilize the transition state for the folding reaction. Pro also functions as a potent folding catalyst when supplied as a separate polypeptide chain, accelerating the rate of αLP folding by a factor of 3 x 109. In the absence of Pro, αLP folds only partially to a stable molten globule-like intermediate state. Addition of Pro to this intermediate leads to rapid formation of native αLP. Here we report the crystal structures of Pro and of the non-covalent inhibitory complex between Pro and native αLP. The C-shaped Pro surrounds the C-terminal β-barrel domain of the folded protease, forming a large complementary interface. Regions of extensive hydration in the interface explain how Pro binds tightly to the native state, yet even more tightly to the folding transition state. Based on structural and functional data we propose that a specific structural element in αLP is largely responsible for the folding barrier and suggest how Pro can overcome this barrier.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 945-950 |
| Number of pages | 6 |
| Journal | Nature Structural Biology |
| Volume | 5 |
| Issue number | 11 |
| DOIs | |
| State | Published - 1998 |
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ASJC Scopus subject areas
- Biochemistry
- Structural Biology
- Genetics
Cite this
Structure of α-lytic protease complexed with its pro region. / Sauter, N. K.; Mau, T.; Rader, S. D.; Agard, D. A.
In: Nature Structural Biology, Vol. 5, No. 11, 1998, p. 945-950.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structure of α-lytic protease complexed with its pro region
AU - Sauter, N. K.
AU - Mau, T.
AU - Rader, S. D.
AU - Agard, D. A.
PY - 1998
Y1 - 1998
N2 - While the majority of proteins fold rapidly and spontaneously to their native states, the extracellular bacterial protease α-lytic protease (αLP) has a t 1/4 for folding of ~2,000 years, corresponding to a folding barrier of 30 kcal mol-1. αLP is synthesized as a pro-enzyme where its pro region (Pro) acts as a foldase to stabilize the transition state for the folding reaction. Pro also functions as a potent folding catalyst when supplied as a separate polypeptide chain, accelerating the rate of αLP folding by a factor of 3 x 109. In the absence of Pro, αLP folds only partially to a stable molten globule-like intermediate state. Addition of Pro to this intermediate leads to rapid formation of native αLP. Here we report the crystal structures of Pro and of the non-covalent inhibitory complex between Pro and native αLP. The C-shaped Pro surrounds the C-terminal β-barrel domain of the folded protease, forming a large complementary interface. Regions of extensive hydration in the interface explain how Pro binds tightly to the native state, yet even more tightly to the folding transition state. Based on structural and functional data we propose that a specific structural element in αLP is largely responsible for the folding barrier and suggest how Pro can overcome this barrier.
AB - While the majority of proteins fold rapidly and spontaneously to their native states, the extracellular bacterial protease α-lytic protease (αLP) has a t 1/4 for folding of ~2,000 years, corresponding to a folding barrier of 30 kcal mol-1. αLP is synthesized as a pro-enzyme where its pro region (Pro) acts as a foldase to stabilize the transition state for the folding reaction. Pro also functions as a potent folding catalyst when supplied as a separate polypeptide chain, accelerating the rate of αLP folding by a factor of 3 x 109. In the absence of Pro, αLP folds only partially to a stable molten globule-like intermediate state. Addition of Pro to this intermediate leads to rapid formation of native αLP. Here we report the crystal structures of Pro and of the non-covalent inhibitory complex between Pro and native αLP. The C-shaped Pro surrounds the C-terminal β-barrel domain of the folded protease, forming a large complementary interface. Regions of extensive hydration in the interface explain how Pro binds tightly to the native state, yet even more tightly to the folding transition state. Based on structural and functional data we propose that a specific structural element in αLP is largely responsible for the folding barrier and suggest how Pro can overcome this barrier.
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U2 - 10.1038/2919
DO - 10.1038/2919
M3 - Article
C2 - 9808037
AN - SCOPUS:0031788058
VL - 5
SP - 945
EP - 950
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
IS - 11
ER -