Structure of α-lytic protease complexed with its pro region

N. K. Sauter, T. Mau, S. D. Rader, D. A. Agard

Research output: Contribution to journalArticle

72 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)945-950
Number of pages6
JournalNature Structural Biology
Volume5
Issue number11
DOIs
StatePublished - 1998

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Peptide Hydrolases
Hydration
Molten materials
Crystal structure
Peptides
Catalysts
Enzymes
Proteins

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 journalArticle

Sauter, N. K. ; Mau, T. ; Rader, S. D. ; Agard, D. A. / Structure of α-lytic protease complexed with its pro region. In: Nature Structural Biology. 1998 ; Vol. 5, No. 11. pp. 945-950.
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