Author/Editor		Staniforth, Rosemary A; Giannini, Silva; Higgins, Lee D; Conroy, Matthew J; Hounslow, Andrea M; Jerala, Roman; Craven, C Jeremy; Waltho, Jonathan P
Title		Three-dimensional domain swapping in the folded and molten-globule states of cystatins, an amyloid-forming structural superfamily
Type		članek
Source		EMBO J
Vol. and No.		Letnik 20, št. 17
Publication year		2001
Volume		str. 4774-81
Language		eng
Abstract		Cystatins, an amyloid-forming structural superfamily, form highly stable, domain-swapped dimers at physiological protein concentrations. In chicken cystatin, the active monomer is a kinetic trap en route to dimerization, and any changes in solution conditions or mutations that destabilize the folded state shorten the lifetime of the monomeric form. In such circumstances, amyloidogenesis will start from conditions where a domain-swapped dimer is the most prevalent species. Domain swapping occurs by a rearrangement of loop I, generating the new intermonomer interface between strands 2 and 3. The transition state for dimerization has a high level of hydrophobic group exposure, indicating that gross conformational perturbation is required for domain swapping to occur. Dimerization also occurs when chicken cystatin is in its reduced, molten-globule state, implying that the organization of secondary structure in this state mirrors that in the folded state and that domain swapping is not limited to the folded states of proteins. Although the interface between cystatin-fold units is poorly defined for cystatin A, the dimers are the appropriate size to account for the electron-dense regions in amyloid protofilaments.
Descriptors		PROTEIN FOLDING CYSTATINS THERMODYNAMICS SEQUENCE HOMOLOGY, AMINO ACID SEQUENCE ALIGNMENT RECOMBINANT PROTEINS PROTEIN STRUCTURE, SECONDARY PROTEIN DENATURATION NUCLEAR MAGNETIC RESONANCE MUTAGENESIS, SITE-DIRECTED MODELS, MOLECULAR KINETICS HYDROGEN BONDING GUANIDINES DIMERIZATION AMINO ACID SEQUENCE CHICKENS