1IJN

Crystal structure of the transthyretin mutant TTR C10A/Y114C

Summary for 1IJN

• Entry DOI: 10.2210/pdb1ijn/pdb
• Related: 1III 1IIK 1IIM
• Descriptor: TRANSTHYRETIN, BETA-MERCAPTOETHANOL (3 entities in total)
• Functional Keywords: greek key, beta barrel, transport protein
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 27839.33

Authors

Eneqvist, T.,Karlsson, A.,Olofsson, A.,Sauer-Eriksson, A.E. (deposition date: 2001-04-27, release date: 2003-06-03, Last modification date: 2023-08-16)

Primary citation

Karlsson, A.,Olofsson, A.,Eneqvist, T.,Sauer-Eriksson, A.E.
Cys114-linked dimers of transthyretin are compatible with amyloid formation
Biochemistry, 44:13063-13070, 2005

PubMed Abstract: The Tyr114Cys substitution in the human plasma protein transthyretin leads to a particularly aggressive form of familial amyloidotic polyneuropathy. In a previous study we demonstrated that ATTR Tyr114Cys forms intermolecular disulfide bonds, which partly impair fibril formation and result in a more amorphous morphology. Apart from the introduced cysteinyl group in position 114, the native sequence contains one cysteine located at position 10. To deduce the role of intermolecular disulfide bridging in fibril formation we generated and characterized the TTR Cys10Ala/Tyr114Cys double mutant. Our results suggest that an intermolecular cysteine bridge at position 114 enhances the exposure of cysteine 10, thereby facilitating additional intermolecular cysteine assemblies. We also purified a disulfide-linked dimeric form of TTR Cys10Ala/Tyr114Cys, which was recognized by the anti-TTR amyloid-specific monoclonal antibody MAb (39-44). Moreover, this dimeric molecule can form protofibrils indistinguishable from the fibrils formed under reducing conditions, as judged by atomic force microscopy. Assuming that both molecules of the dimer are part of the core of the fibril, the assembly is incompatible with a preserved native or near-native dimeric interphase. Our findings raise the question of whether TTR-amyloid architecture is indeed the result of one highly stringent assembly of structures or if different fibrils may be built from different underlying structures.

PubMed: 16185074
DOI: 10.1021/bi050795s

Experimental method

X-RAY DIFFRACTION (1.7 Å)