Molecular mechanisms of amyloid self-regulation
Author: Landreh, Michael
Date: 2012-12-14
Location: Atriumsalen, Nobels väg 12B, Karolinska Institutet, Campus Solna
Time: 09.00
Department: Inst för medicinsk biokemi och biofysik / Dept of Medical Biochemistry and Biophysics
Abstract
Amyloid is associated with both pathological protein deposits and the formation of
functional protein structures. Therefore, several strategies have evolved to control the
formation or inhibition of amyloid in vivo. In this thesis, three separate systems were
investigated in which amyloidogenic protein segments are coupled to regulatory
elements that prevent or promote fibrillation. We describe the molecular mechanism for
how (a) a propeptide segment prevents the uncontrolled aggregation of the mature
peptide, (b) a chaperone domain inhibits amyloid formation, and (c) a pH-dependent
relay controls protein assembly. For this purpose, mass spectrometry (MS)-based
approaches to structural biology were applied and extended, involving gas phase
interaction studies and hydrogen/deuterium exchange MS.
(a) Proinsulin C-peptide is beneficial for the preservation of insulin activity. We show that C-peptide interferes with insulin amyloid fibril formation at low pH and how conserved glutamate residues in C-peptide mediate reversible co-precipitation with insulin. A mechanism is proposed for how the balance between zinc and C-peptide mediates sorting of insulin into slow acting and rapid acting forms inside the secretory granules of the pancreatic -cells, which potentially links C-peptide to diabetes type 1 and 2.
(b) Lung surfactant protein C (SP-C) is a highly amyloidogenic transmembrane polypeptide that controls surface tension in the alveolar phospholipid bilayer. Its proprotein includes a conserved chaperone domain termed BRICHOS, which is also associated with neurodegenerative disorders. It is shown here how BRICHOS and its N-terminal linker recognize hydrophobic residues and trap the SP-C segment in a - hairpin conformation to prevent amyloid formation.
(c) Spider silk is synthesized as a highly soluble protein that assembles into silk in a pH-dependent fashion. It is shown that the spider silk protein N-terminal (NT) domain dimerizes at the same pH interval that triggers silk assembly, and we define the associated structural changes. Furthermore, the use of the NT domain as a solubility tag for the expression of aggregation-prone proteins is demonstrated.
In summary, we have determined the molecular basis for three distinct mechanisms by which fibril formation is controlled through autoregulatory elements and provide insights into nature’s strategies to control amyloid formation and prevention. Based on these findings, we can now make conclusions about nature’s handling of amyloidogenic proteins and their function in general.
(a) Proinsulin C-peptide is beneficial for the preservation of insulin activity. We show that C-peptide interferes with insulin amyloid fibril formation at low pH and how conserved glutamate residues in C-peptide mediate reversible co-precipitation with insulin. A mechanism is proposed for how the balance between zinc and C-peptide mediates sorting of insulin into slow acting and rapid acting forms inside the secretory granules of the pancreatic -cells, which potentially links C-peptide to diabetes type 1 and 2.
(b) Lung surfactant protein C (SP-C) is a highly amyloidogenic transmembrane polypeptide that controls surface tension in the alveolar phospholipid bilayer. Its proprotein includes a conserved chaperone domain termed BRICHOS, which is also associated with neurodegenerative disorders. It is shown here how BRICHOS and its N-terminal linker recognize hydrophobic residues and trap the SP-C segment in a - hairpin conformation to prevent amyloid formation.
(c) Spider silk is synthesized as a highly soluble protein that assembles into silk in a pH-dependent fashion. It is shown that the spider silk protein N-terminal (NT) domain dimerizes at the same pH interval that triggers silk assembly, and we define the associated structural changes. Furthermore, the use of the NT domain as a solubility tag for the expression of aggregation-prone proteins is demonstrated.
In summary, we have determined the molecular basis for three distinct mechanisms by which fibril formation is controlled through autoregulatory elements and provide insights into nature’s strategies to control amyloid formation and prevention. Based on these findings, we can now make conclusions about nature’s handling of amyloidogenic proteins and their function in general.
List of papers:
I. Nerelius, C., Fitzen, M., Johansson, J. (2010) Amino acid sequence determinants and molecular chaperones in amyloid fibril formation. Biochem Biophys Res Commun. 396: 2-6.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Landreh, M., Astorga-Wells, J., Johansson, J., Bergman, T., Jörnvall, H. (2011) New developments in protein structure and function analysis by mass spectrometry and use of H/D exchange microfluidics. FEBS J. 278: 3815–21.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Astorga-Wells, J., Landreh, M., Bergman, T., Jörnvall, H. (2011). A membrane cell for on-line Hydrogen/Deuterium exchange to study protein folding and protein-protein interaction by mass spectrometry. Mol Cell Proteomics. 10: M110.006510.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Landreh, M., Stukenborg, J.-B., Willander, H., Söder, O., Johansson, J., Jörnvall, H. (2012) Proinsulin C-peptide interferes with insulin fibril formation. Biochem Biophys Res Commun. 418: 489-93.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Landreh, M., Alvelius, G., Willander, H., Stukenborg, J.-B., Söder, O., Johansson, J., Jörnvall, H. (2012) Insulin solubility transitions by pHdependent interactions with proinsulin C-peptide. FEBS J. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
VI. Landreh, M., Johansson, J., Jörnvall, H. Interactions of proinsulin Cpeptide in the beta cell secretory granule: A molecular balance with implications for diabetes-associated conditions. [Submitted]
VII. Fitzen, M., Alvelius, G., Nordling, K., Jörnvall, H., Bergman, T., Johansson, J. (2009) Peptide-binding specificity of the prosurfactant protein C Brichos domain analyzed by electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom. 23: 3591-8.
Fulltext (DOI)
Pubmed
View record in Web of Science®
VIII. Willander, H., Askarieh, G., Landreh, M., Westermark, P., Nordling, K., Keränen, H., Hermansson, E., Hamvas, A., Nogee, L.M., Bergman, T., Saenz, A., Casals, C., Åqvist, J., Jörnvall, H., Berglund, H., Presto, J., Knight, S.D., Johansson, J. (2012) High-resolution structure of an intramolecular chaperone. Implications for anti-amyloid activity of the BRICHOS domain. Proc Natl Acad Sci USA. 109: 2325-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IX. Peng, S., Fitzen, M., Jörnvall, H., Johansson, J. (2010). The extracellular domain of Bri2 (ITM2B) binds the ABri peptide (1-23) and amyloid beta-peptide (Abeta1-40). Implications for Bri2 effects on processing of amyloid precursor protein and Abeta aggregation. Biochem Biophys Res Commun. 393: 356-61.
Fulltext (DOI)
Pubmed
View record in Web of Science®
X. Landreh, M., Askarieh, G., Nordling, K., Hedhammar, M., Rising, A., Astorga-Wells, J., Alvelius, G., Casals, C., Knight, S. D., Johansson, J., Jörnvall, H., and Bergman, T. (2010) A pH-dependent dimer lock in spider silk protein. J Mol Biol. 404: 328-36.
Fulltext (DOI)
Pubmed
View record in Web of Science®
XI. Jaudzems, K., Askarieh, G., Landreh, M., Nordling, K., Hedhammar, M., Jörnvall, H., Rising, A., Knight, S. D., and Johansson, J. (2012) pH-dependent dimerization of spider silk N-terminal domain requires relocation of a wedged tryptophan side-chain. J Mol Biol. 422: 477-87.
Fulltext (DOI)
Pubmed
View record in Web of Science®
XII. Rising, A., Nordling, K, Landreh, M., Lindqvist, A., Johansson, J. The N-terminal domain of spider silk proteins as solubility-enhancing tag for recombinant protein production. [Manuscript]
XIII. Landreh, M., Johansson, J., Rising, A., Presto, J., and Jörnvall, H. (2012) Control of amyloid assembly by autoregulation. Biochem J. 447: 185-92.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Nerelius, C., Fitzen, M., Johansson, J. (2010) Amino acid sequence determinants and molecular chaperones in amyloid fibril formation. Biochem Biophys Res Commun. 396: 2-6.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Landreh, M., Astorga-Wells, J., Johansson, J., Bergman, T., Jörnvall, H. (2011) New developments in protein structure and function analysis by mass spectrometry and use of H/D exchange microfluidics. FEBS J. 278: 3815–21.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Astorga-Wells, J., Landreh, M., Bergman, T., Jörnvall, H. (2011). A membrane cell for on-line Hydrogen/Deuterium exchange to study protein folding and protein-protein interaction by mass spectrometry. Mol Cell Proteomics. 10: M110.006510.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Landreh, M., Stukenborg, J.-B., Willander, H., Söder, O., Johansson, J., Jörnvall, H. (2012) Proinsulin C-peptide interferes with insulin fibril formation. Biochem Biophys Res Commun. 418: 489-93.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Landreh, M., Alvelius, G., Willander, H., Stukenborg, J.-B., Söder, O., Johansson, J., Jörnvall, H. (2012) Insulin solubility transitions by pHdependent interactions with proinsulin C-peptide. FEBS J. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
VI. Landreh, M., Johansson, J., Jörnvall, H. Interactions of proinsulin Cpeptide in the beta cell secretory granule: A molecular balance with implications for diabetes-associated conditions. [Submitted]
VII. Fitzen, M., Alvelius, G., Nordling, K., Jörnvall, H., Bergman, T., Johansson, J. (2009) Peptide-binding specificity of the prosurfactant protein C Brichos domain analyzed by electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom. 23: 3591-8.
Fulltext (DOI)
Pubmed
View record in Web of Science®
VIII. Willander, H., Askarieh, G., Landreh, M., Westermark, P., Nordling, K., Keränen, H., Hermansson, E., Hamvas, A., Nogee, L.M., Bergman, T., Saenz, A., Casals, C., Åqvist, J., Jörnvall, H., Berglund, H., Presto, J., Knight, S.D., Johansson, J. (2012) High-resolution structure of an intramolecular chaperone. Implications for anti-amyloid activity of the BRICHOS domain. Proc Natl Acad Sci USA. 109: 2325-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IX. Peng, S., Fitzen, M., Jörnvall, H., Johansson, J. (2010). The extracellular domain of Bri2 (ITM2B) binds the ABri peptide (1-23) and amyloid beta-peptide (Abeta1-40). Implications for Bri2 effects on processing of amyloid precursor protein and Abeta aggregation. Biochem Biophys Res Commun. 393: 356-61.
Fulltext (DOI)
Pubmed
View record in Web of Science®
X. Landreh, M., Askarieh, G., Nordling, K., Hedhammar, M., Rising, A., Astorga-Wells, J., Alvelius, G., Casals, C., Knight, S. D., Johansson, J., Jörnvall, H., and Bergman, T. (2010) A pH-dependent dimer lock in spider silk protein. J Mol Biol. 404: 328-36.
Fulltext (DOI)
Pubmed
View record in Web of Science®
XI. Jaudzems, K., Askarieh, G., Landreh, M., Nordling, K., Hedhammar, M., Jörnvall, H., Rising, A., Knight, S. D., and Johansson, J. (2012) pH-dependent dimerization of spider silk N-terminal domain requires relocation of a wedged tryptophan side-chain. J Mol Biol. 422: 477-87.
Fulltext (DOI)
Pubmed
View record in Web of Science®
XII. Rising, A., Nordling, K, Landreh, M., Lindqvist, A., Johansson, J. The N-terminal domain of spider silk proteins as solubility-enhancing tag for recombinant protein production. [Manuscript]
XIII. Landreh, M., Johansson, J., Rising, A., Presto, J., and Jörnvall, H. (2012) Control of amyloid assembly by autoregulation. Biochem J. 447: 185-92.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Bergman, Tomas
Issue date: 2012-11-01
Rights:
Publication year: 2012
ISBN: 978-91-7457-974-1
Statistics
Total Visits
Views | |
---|---|
Molecular ...(legacy) | 1050 |
Molecular ... | 316 |
Total Visits Per Month
March 2024 | April 2024 | May 2024 | June 2024 | July 2024 | August 2024 | September 2024 | |
---|---|---|---|---|---|---|---|
Molecular ... | 4 | 1 | 0 | 4 | 4 | 3 | 2 |
File Visits
Views | |
---|---|
Thesis_Michael_Landreh.pdf(legacy) | 1227 |
Thesis_Michael_Landreh.pdf | 359 |
Spikblad_Michael_Landreh.pdf(legacy) | 229 |
Spikblad_Michael_Landreh.pdf | 46 |
Thesis_Michael_Landreh.pdf.txt(legacy) | 2 |
Spikblad_Michael_Landreh.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 499 |
Sweden | 201 |
Germany | 86 |
China | 83 |
South Korea | 29 |
Denmark | 27 |
United Kingdom | 25 |
Russia | 21 |
India | 19 |
France | 15 |
Top cities views
Views | |
---|---|
Ashburn | 67 |
Stockholm | 54 |
Romeo | 43 |
Sunnyvale | 42 |
Beijing | 24 |
Kiez | 22 |
Ballerup | 21 |
Seoul | 19 |
Uppsala | 14 |
London | 13 |