1r4c

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spinqualitylabelsall models 1r4c, resolution 2.18Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

N-Truncated Human Cystatin C; Dimeric Form With 3D Domain Swapping

Overview

Human cystatin C (HCC) inhibits papain-like cysteine proteases by a, binding epitope composed of two beta-hairpin loops and the N-terminal, segment. HCC is found in all body fluids and is present at a particularly, high level in the cerebrospinal fluid. Oligomerization of HCC leads to, amyloid deposits in brain arteries at advanced age but this pathological, process is greatly accelerated with a naturally occurring Leu68Gln, variant, resulting in fatal amyloidosis in early adult life. When proteins, are extracted from human cystatin C amyloid deposits, an N-terminally, truncated cystatin C (THCC) is found, lacking the first ten amino acid, residues of the native sequence. It has been shown that the cerebrospinal, fluid may cause this N-terminal truncation, possibly because of, disintegration of the leucocytes normally present in this fluid, and the, release of leucocyte proteolytic enzymes. HCC is the first disease-causing, amyloidogenic protein for which oligomerization via 3D domain swapping has, been observed. The aggregates arise in the crystallization buffer and have, the form of 2-fold symmetric dimers in which a long alpha-helix of one, molecule, flanked by two adjacent beta-strands, has replaced an identical, domain of the other molecule, and vice versa. Consistent with a, conformational change at one of the beta-hairpin loops of the binding, epitope, the dimers (and also any other oligomers, including amyloid, aggregates) are inactive as papain inhibitors. Here, we report the, structure of N-truncated HCC, the dominant form of cystatin C in amyloid, deposits. Although the protein crystallized under conditions that are, drastically different from those for the full-length protein, the, structure reveals dimerization by the same act of domain swapping., However, the new crystal structure is composed of four independent HCC, dimers, none of which has the exact 2-fold symmetry of the full-length, dimer. While the four dimers have the same overall topology, the exact, relation between the individual domains shows a variability that reflects, the flexibility at the dimer-specific open interface, which in the case of, 3D domain-swapped HCC consists of beta-interactions between the open hinge, loops and results in an unusually long intermolecular beta-sheet. The, dimers are engaged in further quaternary interactions resulting in, spherical, closed octameric assemblies that are identical to that present, in the crystal of the full-length protein. The octamers interact via, hydrophobic patches formed on the surface of the domain-swapped dimers as, well as by extending the dimer beta-sheet through intermolecular contacts.

About this Structure

1R4C is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Domain swapping in N-truncated human cystatin C., Janowski R, Abrahamson M, Grubb A, Jaskolski M, J Mol Biol. 2004 Jul 30;341(1):151-60. PMID:15312769

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