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Sci Rep. 2019 Feb 28;9(1):3123. doi: 10.1038/s41598-019-39781-3.

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

Author information

1
Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Delegación Tlalpan, Ciudad de México, 14610, Mexico.
2
School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QG, United Kingdom.
3
Chemistry Department, College of Science, Mustansiriyah University, Baghdad, Iraq.
4
Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, 62210, Morelos, Mexico.
5
Centro de Desarrollo de Productos Bióticos, Instituto Politécnico Nacional, Carr. Yautepec-Jojutla Km 6, Calle CEPROBI No. 8, Col. San Isidro, Yautepec, 62731, Morelos, Mexico.
6
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center Shreveport, 1501 Kings Hwy, Shreveport, LA, 71103, USA.
7
Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Delegación Tlalpan, Ciudad de México, 14610, Mexico. ldelpo@lsuhsc.edu.
8
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center Shreveport, 1501 Kings Hwy, Shreveport, LA, 71103, USA. ldelpo@lsuhsc.edu.

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 regions of the protein. It was shown that a fibrillogenic hotspot associated to the CDR1 is also encoded by several κ and λ germline variable domain gene segments. Some parts of this study have been included in the chapter "The Structural Determinants of the Immunoglobulin Light Chain Amyloid Aggregation", published in Physical Biology of Proteins and Peptides, Springer 2015 (ISBN 978-3-319-21687-4).

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