Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis

P. Patrizia Mangione; Riccardo Porcari; Julian D. GillmorePiero PucciMaria MontiMattia PorcariSofia GiorgettiLoredana MarcheseSara RaimondiLouise C. SerpellWenjie ChenAnnalisa ReliniJulien MarcouxInnes R. ClatworthyGraham W. TaylorGlenys A. TennentCarol V. RobinsonPhilip N. HawkinsMonica StoppiniStephen P. WoodMark B. PepysVittorio Bellotti

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis

【24h】

Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis

机译：Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis

获取原文

获取原文并翻译 | 示例

掌桥外文数据库（机构版） >>

开具论文收录证明 >>

文献代查 >>

页面导航

摘要
著录项
相关主题

摘要

The Ser52Pro variant of transthyretin (TTR) produces aggressive, highly penetrant, autosomal-dominant systemic amyloidosis in persons heterozygous for the causative mutation. Together with a minor quantity of full-length wild-type and variant TTR, the main component of the ex vivo fibrils was the residue 49-127 fragment of the TTR variant, the portion of the TTR sequence that previously has been reported to be the principal constituent of type A, cardiac amyloid fibrils formed from wild-type TTR and other TTR variants Bergstrom J, et al. (2005) J Pathol 206(2):224-232. This specific truncation of Ser52Pro TTR was generated readily in vitro by limited proteolysis. In physiological conditions and under agitation the residue 49-127 proteolytic fragment rapidly and completely self-aggregates into typical amyloid fibrils. The remarkable susceptibility to such cleavage is likely caused by localized destabilization of the β-turn linking strands C and D caused by loss of the wildtype hydrogen-bonding network between the side chains of residues Ser52, Glu54, Ser50, and a water molecule, as revealed by the high-resolution crystallographic structure of Ser52Pro TTR. We thus provide a structural basis for the recently hypothesized, crucial pathogenic role of proteolytic cleavage in TTR amyloid fibrillogenesis. Binding of the natural ligands thyroxine or retinol-binding protein (RBP) by Ser52Pro variant TTR stabilizes the native tetrameric assembly, but neither protected the variant from proteolysis. However, binding of RBP, but not thyroxine, inhibited subsequent fibrillogenesis.

著录项

来源
《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第4期|1539-1544|共6页
作者
P. Patrizia Mangione; Riccardo Porcari; Julian D. GillmorePiero PucciMaria MontiMattia PorcariSofia GiorgettiLoredana MarcheseSara RaimondiLouise C. SerpellWenjie ChenAnnalisa ReliniJulien MarcouxInnes R. ClatworthyGraham W. TaylorGlenys A. TennentCarol V. RobinsonPhilip N. HawkinsMonica StoppiniStephen P. WoodMark B. PepysVittorio Bellotti;
展开▼
作者单位

Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, United Kingdom;

Department of Chemical Sciences, University of Naples Federico II, 80145 Naples, Italy;

Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, ItalySchool of Life Sciences, University of Sussex, Falmer BN1 9QG, United KingdomLaboratory of Protein Crystallography, Centre for Amyloidosis and Acute Phase Proteins, University College London, London NW3 2PF, United KingdomDepartment of Physics, University of Genoa, 16146 Genoa, ItalyDepartment of Chemistry, University of Oxford, Oxford OX1 3TA, United KingdomElectron Microscopy Unit, University College London, London NW3 2PF, United Kingdom;

展开▼
收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
misfolding; protein aggregation;

Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis

摘要

著录项

相关主题

期刊订阅