Linked Life Data

11297418

Source:http://linkedlifedata.com/resource/pubmed/id/11297418

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2001-4-12
pubmed:abstractText
Light chain, or AL, amyloidosis is a pathological condition arising from systemic extracellular deposition of monoclonal immunoglobulin light chain variable domains in the form of insoluble amyloid fibrils, especially in the kidneys. Substantial evidence suggests that amyloid fibril formation from native proteins occurs via a conformational change leading to a partially folded intermediate conformation, whose subsequent association is a key step in fibrillation. In the present investigation, we have examined the properties of a recombinant amyloidogenic light chain variable domain, SMA, to determine whether partially folded intermediates can be detected and correlated with aggregation. The results from spectroscopic and hydrodynamic measurements, including far- and near-UV circular dichroism, FTIR, NMR, and intrinsic tryptophan fluorescence and small-angle X-ray scattering, reveal the build-up of two partially folded intermediate conformational states as the pH is decreased (low pH destabilized the protein and accelerated the kinetics of aggregation). A relatively nativelike intermediate, I(N), was observed between pH 4 and 6, with little loss of secondary structure, but with significant tertiary structure changes and enhanced ANS binding, indicating exposed hydrophobic surfaces. At pH below 3, we observed a relatively unfolded, but compact, intermediate, I(U), which was characterized by decreased tertiary and secondary structure. The I(U) intermediate readily forms amyloid fibrils, whereas I(N) preferentially leads to amorphous aggregates. Except at pH 2, where negligible amorphous aggregate is formed, the amorphous aggregates formed significantly more rapidly than the fibrils. This is the first indication that different partially folded intermediates may be responsible for different aggregation pathways (amorphous and fibrillar). The data support the hypothesis that amyloid fibril formation involves the ordered self-assembly of partially folded species that are critical soluble precursors of fibrils.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
27
pubmed:volume
40
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3525-35
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:11297418-Amyloid, pubmed-meshheading:11297418-Amyloidosis, pubmed-meshheading:11297418-Circular Dichroism, pubmed-meshheading:11297418-Humans, pubmed-meshheading:11297418-Immunoglobulin Light Chains, pubmed-meshheading:11297418-Immunoglobulin Variable Region, pubmed-meshheading:11297418-Kinetics, pubmed-meshheading:11297418-Microscopy, Atomic Force, pubmed-meshheading:11297418-Nuclear Magnetic Resonance, Biomolecular, pubmed-meshheading:11297418-Protein Conformation, pubmed-meshheading:11297418-Protein Folding, pubmed-meshheading:11297418-Protein Precursors, pubmed-meshheading:11297418-Scattering, Radiation, pubmed-meshheading:11297418-Spectrometry, Fluorescence, pubmed-meshheading:11297418-Spectroscopy, Fourier Transform Infrared, pubmed-meshheading:11297418-Thermodynamics, pubmed-meshheading:11297418-X-Rays
pubmed:year
2001
pubmed:articleTitle
Partially folded intermediates as critical precursors of light chain amyloid fibrils and amorphous aggregates.
pubmed:affiliation
Department of Chemistry and Biochemistry, University of California, Santa Cruz 95064, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't