Fibril Growth Kinetics Reveal a Region of beta(2)-microglobulin Important for Nucleation and Elongation of Aggregation.

Fibril Growth Kinetics Reveal a Region of beta(2)-microglobulin Important for Nucleation and Elongation of Aggregation. Research Abstract Details 

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Fibril Growth Kinetics Reveal a Region of beta(2)-microglobulin Important for Nucleation and Elongation of Aggregation. Abstract Text:

Geoffrey W Platt,Katy E Routledge,Steve W Homans,Sheena E Radford,Geoffrey W Platt,Katy E Routledge,Steve W Homans,Sheena E Radford,

Amyloid is a highly ordered form of aggregate comprising long, straight and unbranched proteinaceous fibrils that are formed with characteristic nucleation-dependent kinetics in vitro. Currently, the structural molecular mechanism of fibril nucleation and elongation is poorly understood. Here, we investigate the role of the sequence and structure of the initial monomeric precursor in determining the rates of nucleation and elongation of human beta(2)-microglobulin (beta(2)m). We describe the kinetics of seeded and spontaneous (unseeded) fibril growth of wild-type beta(2)m and 12 variants at pH 2.5, targeting specifically an aromatic-rich region of the polypeptide chain (residues 62-70) that has been predicted to be highly amyloidogenic. The results reveal the importance of aromatic residues in this part of the beta(2)m sequence in fibril formation under the conditions explored and show that this region of the polypeptide chain is involved in both the nucleation and the elongation phases of fibril formation. Structural analysis of the conformational properties of the unfolded monomer for each variant using NMR relaxation methods revealed that all variants contain significant non-random structure involving two hydrophobic clusters comprising regions 29-51 and 58-79, the extent of which is critically dependent on the sequence. No direct correlation was observed, however, between the extent of non-random structure in the unfolded state and the rates of fibril nucleation and elongation, suggesting that the early stages of aggregation involve significant conformational changes from the initial unfolded state. Together, the data suggest a model for beta(2)m amyloid formation in which structurally specific interactions involving the highly hydrophobic and aromatic-rich region comprising residues 62-70 provide a complementary interface that is key to the generation of amyloid fibrils for this protein at acidic pH.

Fibril Growth Kinetics Reveal a Region of beta(2)-microglobulin Important for Nucleation and Elongation of Aggregation. Publishing Authors By Initials

GW Platt,KE Routledge,SW Homans,SE Radford,GW Platt,KE Routledge,SW Homans,SE Radford,

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Fibril Growth Kinetics Reveal a Region of beta(2)-microglobulin Important for Nucleation and Elongation of Aggregation. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Journal of molecular biology

VOLUME: 378

Page Numbers: 251-63

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ISSN: 1089-8638

DAY: 12

MONTH: 02

YEAR: 2008

Fibril Growth Kinetics Reveal a Region of beta(2)-microglobulin Important for Nucleation and Elongation of Aggregation. Information

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LANGUAGE: eng

NlmUniqueID: 2985088

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Grant and Affiliation Information for Fibril Growth Kinetics Reveal a Region of beta(2)-microglobulin Important for Nucleation and Elongation of Aggregation.

AFFILIATION: Astbury Centre for Structural Molecular Biology and Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.

Country: England

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MEDLINETA: J Mol Biol

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