PDBsum entry 2znh

Blood clotting

PDB id: 2znh

Contents

Protein chain

408 a.a. *

Ligands

NAG-NAG

NAG-NAG-MAN ×2

NAG ×2

CIT ×2

Waters ×91

* Residue conservation analysis

PDB id:

2znh

Name:

Blood clotting

Title:

Crystal structure of a domain-swapped serpin dimer

Structure:

Antithrombin-iii. Chain: a, b. Synonym: atiii

Source:

Homo sapiens. Human. Organism_taxid: 9606. Other_details: from blood plasma

Resolution:

2.80Å R-factor: 0.201 R-free: 0.247

Authors:

M.Yamasaki,J.A.Huntington

Key ref:

M.Yamasaki et al. (2008). Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. Nature, 455, 1255-1258. PubMed id: 18923394 DOI: 10.1038/nature07394

Date:

25-Apr-08 Release date: 21-Oct-08

Protein chains

P01008  (ANT3_HUMAN) -  Antithrombin-III from Homo sapiens

Seq: 464 a.a.

Struc: 408 a.a.

DOI no: 10.1038/nature07394

Nature 455:1255-1258 (2008)

PubMed id: 18923394

Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization.

M.Yamasaki, W.Li, D.J.Johnson, J.A.Huntington.

ABSTRACT

Repeating intermolecular protein association by means of beta-sheet expansion is the mechanism underlying a multitude of diseases including Alzheimer's, Huntington's and Parkinson's and the prion encephalopathies. A family of proteins, known as the serpins, also forms large stable multimers by ordered beta-sheet linkages leading to intracellular accretion and disease. These 'serpinopathies' include early-onset dementia caused by mutations in neuroserpin, liver cirrhosis and emphysema caused by mutations in alpha(1)-antitrypsin (alpha(1)AT), and thrombosis caused by mutations in antithrombin. Serpin structure and function are quite well understood, and the family has therefore become a model system for understanding the beta-sheet expansion disorders collectively known as the conformational diseases. To develop strategies to prevent and reverse these disorders, it is necessary to determine the structural basis of the intermolecular linkage and of the pathogenic monomeric state. Here we report the crystallographic structure of a stable serpin dimer which reveals a domain swap of more than 50 residues, including two long antiparallel beta-strands inserting in the centre of the principal beta-sheet of the neighbouring monomer. This structure explains the extreme stability of serpin polymers, the molecular basis of their rapid propagation, and provides critical new insights into the structural changes which initiate irreversible beta-sheet expansion.

Selected figure(s)

Figure 1.
Figure 1: Crystallographic structures of active, latent and self-terminating dimer of the serpin antithrombin. a, Active antithrombin is shown with the RCL on top (yellow) and the -sheet A facing (red, with numbered strands). Either by proteolytic cleavage in the RCL or by extraction of strand 1C (s1C, orange), serpins incorporate the RCL into -sheet A as strand 4A (s4A) resulting in a hyperstable six-stranded conformation. Polymerogenic mutations are shown (yellow is Z, magenta is Mmalton, blue is Siiyama and Syracuse, red and cyan are His338Arg and Gly392Glu neuroserpin^3, and green is P80S antithrombin^11). The loop connecting strand 6A to 5A is in cyan. b, The latent conformer of antithrombin is shown coloured as in a. Residues on strands 5 and 6A, which were mutated to Cys (see Fig. 2a), are indicated by green balls. c, The structure of the stable antithrombin dimer (monomer A coloured as in b, and monomer B is pale green).

Figure 3.
Figure 3: Models of the serpin polymer and the M* state. a, A model of a linear serpin dimer (coloured as in Fig. 1c), with balls indicating AspN cleavage sites found in polymers of antithrombin (magenta) and [1]AT (cyan). The yellow ball shows the position of the Leu303Cys substitution (Fig. 2c). b, A modelled pentamer was formed by the addition of protomers to both ends of the dimer. c, A model of the polymerogenic folding intermediate (M*) with the contiguous loop from the C terminus of strand 6A to strand 1C in a random-coil conformation. New proteolytic sites in this region (magenta balls for antithrombin, cyan balls for [1]AT and green balls for PAI-1; ref. 20) were detected for the M* state (Fig. 2d).

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2008, 455, 1255-1258) copyright 2008.

Figures were selected by the author.