The CDR1 and Other Regions of Immunoglobulin Light Chains are Hot Spots for Amyloid Aggregation

Scientific Reports
Robin Axel Ruiz-ZamoraLuis del Pozo-Yauner

Abstract

Immunoglobulin light chain-derived (AL) amyloidosis is a debilitating disease without known cure. Almost nothing is known about the structural factors driving the amyloidogenesis of the light chains. This study aimed to identify the fibrillogenic hotspots of the model protein 6aJL2 and in pursuing this goal, two complementary approaches were applied. One of them was based on several web-based computational tools optimized to predict fibrillogenic/aggregation-prone sequences based on different structural and biophysical properties of the polypeptide chain. Then, the predictions were confirmed with an ad-hoc synthetic peptide library. In the second approach, 6aJL2 protein was proteolyzed with trypsin, and the products incubated in aggregation-promoting conditions. Then, the aggregation-prone fragments were identified by combining standard proteomic methods, and the results validated with a set of synthetic peptides with the sequence of the tryptic fragments. Both strategies coincided to identify a fibrillogenic hotspot located at the CDR1 and β-strand C of the protein, which was confirmed by scanning proline mutagenesis analysis. However, only the proteolysis-based strategy revealed additional fibrillogenic hotspots in two other ...Continue Reading

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Citations

Dec 20, 2018·Chembiochem : a European Journal of Chemical Biology·Lauriane LecoqAnja Böckmann
Dec 7, 2020·Journal of Molecular Biology·Gunasekhar BurraAshwani K Thakur
Jan 29, 2021·The Journal of Biological Chemistry·Georg J RottenaicherJohannes Buchner
May 1, 2021·Biochemical Society Transactions·Marcus Fändrich, Matthias Schmidt

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Methods Mentioned

BETA
Aggregation
Circular Dichroism
X-ray
nuclear magnetic resonance
transmission electron microscopy

Software Mentioned

CSSP2
PyMOL
Net
FindPept
RosettaDesign
ZipperDB
PROTPARAM
CLEARER
Rosetta
CSSP

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