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Commentary & View

New insight into serpin polymerization and aggregation

, &
Pages 12-14 | Received 13 Nov 2009, Accepted 16 Mar 2009, Published online: 01 Jan 2009
 

Abstract

We recently solved the crystallographic structure of a dimeric form of the serpin antithrombin which has fundamentally changed the way we think about serpin polymerization. Like for other diseases that have protein deposition as a hallmark, the serpinopathies are associated with discrete inter-protomer linkage followed by subsequent association into larger fibrils and aggregates. Polymerization of the serpins is an off-pathway event that occurs during folding in the endoplasmic reticulum. Our structure reveals the nature of the polymerogenic folding intermediate, the reason that the inter-protomer linkage is hyperstable, and suggests a mechanism of lateral association of polymers into soluble fibrils and insoluble aggregates. While the basis of cellular toxicity is still unclear, novel therapeutic approaches targeting the folding intermediate or the lateral association event are now conceivable.

Figures and Tables

Figure 1 Serpin folding and polymerization. The pathway of serpin folding proceeds from the unfolded state (U) to the native state (N) via a stable intermediate (M*). The native conformation is the only active state, and is composed of a five-stranded A sheet (red) and a 20 residue reactive centre loop (RCL, yellow). Serpin inhibitory function requires the native conformation to be a kinetically trapped metastable state. Completion of sheet A by incorporation of the RCL as strand 4, to form the latent (L) state, results in the doubling of the serpin's thermodynamic stability (the six strands are labelled on L). Folding and unfolding of native serpins is known to proceed via a stable intermediate denoted M*, which also corresponds to the polymerogenic form.Citation24Citation26 The key feature of the M* state is that strand 5 is not yet incorporated into sheet A, and can thus insert in an intermolecular fashion to form off-pathway polymers (P, each protomer of the pentamer is in a different colour). The polymers have complete A sheets and are thus hyperstable. As a consequence of polymerization, the linker region (cyan), containing helix I, remains unfolded. We hypothesize that the hydrophobic linker (indicated by the oval) is responsible for the lateral association of polymers into insoluble aggregates.

Figure 1 Serpin folding and polymerization. The pathway of serpin folding proceeds from the unfolded state (U) to the native state (N) via a stable intermediate (M*). The native conformation is the only active state, and is composed of a five-stranded A sheet (red) and a 20 residue reactive centre loop (RCL, yellow). Serpin inhibitory function requires the native conformation to be a kinetically trapped metastable state. Completion of sheet A by incorporation of the RCL as strand 4, to form the latent (L) state, results in the doubling of the serpin's thermodynamic stability (the six strands are labelled on L). Folding and unfolding of native serpins is known to proceed via a stable intermediate denoted M*, which also corresponds to the polymerogenic form.Citation24–Citation26 The key feature of the M* state is that strand 5 is not yet incorporated into sheet A, and can thus insert in an intermolecular fashion to form off-pathway polymers (P, each protomer of the pentamer is in a different colour). The polymers have complete A sheets and are thus hyperstable. As a consequence of polymerization, the linker region (cyan), containing helix I, remains unfolded. We hypothesize that the hydrophobic linker (indicated by the oval) is responsible for the lateral association of polymers into insoluble aggregates.

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