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Heparan sulfate/hep...
Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein
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- Noborn, Fredrik (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Jin-ping Li,Department of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Husargatan 3, Box 582, 751 23 Uppsala, Sweden
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- O'Callaghan, Paul (author)
- Uppsala universitet,Geriatrik,Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 751 85 Uppsala, Sweden
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- Hermansson, Erik (author)
- Karolinska Institutet
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- Zhang, Xiao (author)
- Uppsala universitet,Geriatrik,Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 751 85 Uppsala, Sweden
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- Ancsin, John (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Department of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Husargatan 3, Box 582, 751 23 Uppsala, Sweden
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- Damas, Ana (author)
- Molecular Structure Group, Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal
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- Dacklin, Ingrid (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)
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- Presto, Jenny (author)
- Karolinska Institutet
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- Johansson, Jan (author)
- Karolinska Institutet
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Saraiva, Maria (author)
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- Lundgren, Erik (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)
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- Kisilevsky, Robert (author)
- Department of Pathology and Molecular Medicine, Richardson Laboratory, 88 Stuart Street, Queen’s University, Kingston, ON, Canada K7L 3N6
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- Westermark, Per (author)
- Uppsala universitet,Institutionen för genetik och patologi,Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 751 85 Uppsala, Sweden
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- Li, Jin-ping (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Department of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Husargatan 3, Box 582, 751 23 Uppsala, Sweden
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(creator_code:org_t)
- 2011-03-21
- 2011
- English.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:14, s. 5584-5589
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Abstract
Subject headings
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- Transthyretin (TTR) is a homotetrameric protein that transports thyroxine and retinol. Tetramer destabilization and misfolding of the released monomers result in TTR aggregation, leading to its deposition as amyloid primarily in the heart and peripheral nervous system. Over 100 mutations of TTR have been linked to familial forms of TTR amyloidosis. Considerable effort has been devoted to the study of TTR aggregation of these mutants, although the majority of TTR-related amyloidosis is represented by sporadic cases due to the aggregation and deposition of the otherwise stable wild-type (WT) protein. Heparan sulfate (HS) has been found as a pertinent component in a number of amyloid deposits, suggesting its participation in amyloidogenesis. This study aimed to investigate possible roles of HS in TTR aggregation. Examination of heart tissue from an elderly cardiomyopathic patient revealed substantial accumulation of HS associated with the TTR amyloid deposits. Studies demonstrated that heparin/HS promoted TTR fibrillization through selective interaction with a basic motif of TTR. The importance of HS for TTR fibrillization was illustrated in a cell model; TTR incubated with WT Chinese hamster ovary cells resulted in fibrillization of the protein, but not with HS-deficient cells (pgsD-677). The effect of heparin on TTR fibril formation was further demonstrated in a Drosophila model that overexpresses TTR. Heparin was colocalized with TTR deposits in the head of the flies reared on heparin-supplemented medium, whereas no heparin was detected in the nontreated flies. Heparin of low molecular weight (Klexane) did not demonstrate this effect.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- transthyretin
- amyloid
- heparan sulfate
- heparin
- cardiomyopathy
- Medical Biochemistry
- Medicinsk biokemi
- biology
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Noborn, Fredrik
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O'Callaghan, Pau ...
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Hermansson, Erik
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Zhang, Xiao
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Ancsin, John
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Damas, Ana
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show more...
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Dacklin, Ingrid
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Presto, Jenny
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Johansson, Jan
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Saraiva, Maria
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Lundgren, Erik
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Kisilevsky, Robe ...
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Westermark, Per
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Li, Jin-ping
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Proceedings of t ...
- By the university
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Uppsala University
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Umeå University
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Karolinska Institutet