PDBsum entry 3e4c

Hydrolase

PDB id: 3e4c

Contents

Protein chain

271 a.a. *

Metals

_MG

Waters ×136

* Residue conservation analysis

PDB id:

3e4c

Name:

Hydrolase

Title:

Procaspase-1 zymogen domain crystal structure

Structure:

Caspase-1. Chain: a, b. Fragment: procaspase-1 zymogen domain (unp residues 104-404). Synonym: casp-1, interleukin-1 beta convertase, il-1bc, interleukin-1 beta-converting enzyme, il-1 beta-converting enzyme, ice, p45, caspase-1 subunit p20, caspase-1 subunit p10. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Strain: human RNA isolate. Gene: casp1, il1bc, il1bce. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.05Å R-factor: 0.204 R-free: 0.263

Authors:

J.M.Elliott,L.Rouge,C.Wiesmann,J.M.Scheer

Key ref:

J.M.Elliott et al. (2009). Crystal structure of procaspase-1 zymogen domain reveals insight into inflammatory caspase autoactivation. J Biol Chem, 284, 6546-6553. PubMed id: 19117953 DOI: 10.1074/jbc.M806121200

Date:

11-Aug-08 Release date: 30-Dec-08

Protein chains

P29466  (CASP1_HUMAN) -  Caspase-1 from Homo sapiens

Seq: 404 a.a.

Struc: 271 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.22.36 - caspase-1.
• Reaction: Release of interleukin 1-beta by specific cleavage at 116-Asp-|-Ala-117 and 27-Asp-|-Gly-28 bonds in precursor. Also hydrolyzes the small- molecule substrate, Ac-Tyr-Val-Ala-Asp-|-NHMec.

DOI no: 10.1074/jbc.M806121200

J Biol Chem 284:6546-6553 (2009)

PubMed id: 19117953

Crystal structure of procaspase-1 zymogen domain reveals insight into inflammatory caspase autoactivation.

J.M.Elliott, L.Rouge, C.Wiesmann, J.M.Scheer.

ABSTRACT

One key event in inflammatory signaling is the activation of the initiator caspase, procaspase-1. Presented here is the crystal structure of the procaspase-1 zymogen without its caspase recruitment domain solved to 2.05 A. Although the isolated domain is monomeric in solution, the protein appeared dimeric in crystals. The loop arrangements in the dimer provide insight into the first autoproteolytic events that occur during activation by oligomerization. Additionally, in contrast to other caspases, we demonstrate that autoproteolysis at the second cleavage site, Asp316, is necessary for conversion to a stable dimer in solution. Critical elements of secondary structure are revealed in the crystal structure that explain why a dimeric protein is favored after proteolysis at this aspartic acid. Dimer stabilization is concurrent with a 130-fold increase in kcat, the sole contributing kinetic factor to an activated and efficient mediator of inflammation.

Selected figure(s)

Figure 4.
Structural comparison of initiator and effector caspase zymogens. A, procaspase-1 (PDB code 3E4C) shown as a schematic with the linker region shown as a thick ribbon. Both aspartic acid cleavage sites between the p20 and p10 in one monomer are shown as spheres. The dotted line represents unresolved residues not seen in the electron density maps. B, schematic representation of procaspase-7 (PDB code 1GQF (25)), an effector caspase, with the interdomain linker shown as a thick ribbon. Only the first site of processing in effector caspases is required for activation. It is noticeable that the first cleavage site is up and away from the dimer interface in caspase-7.

Figure 5.
Key structural elements of caspase-1 dimer stabilization. A, schematic representation of caspase-1 zymogen (left, PDB code 3E4C) and processed ligand-free caspase-1 (right, PDB code 1SC1 (42)). The proenzyme shows a well defined α-helix near the putative N terminus of the p10. This element contains cleavage Site 2, which is the critical processing site for caspase-1 activation. Once proteolysis occurs at Asp^316, the newly formed p20 C terminus and p10 N terminus are able to form anti-parallel β-sheets in the active enzyme. The important secondary structural elements are indicated with red circles. B, diagram of the backbone atoms of residues 314-321. Brackets indicate backbone interactions in the α-helix in the proenzyme structure. Two of the three hydrogen bonds in the helix are severed upon proteolysis at Asp^316, indicated with an arrow.

The above figures are reprinted from an Open Access publication published by the ASBMB: J Biol Chem (2009, 284, 6546-6553) copyright 2009.

Figures were selected by the author.