The CDR1 and Other Regions of Immunoglobulin Light Chains are Hot Spots for Amyloid Aggregation
Por:
Ruiz-Zamora, Robin Axel, Guillaume, Simon, Al-Hilaly, Youssra K., Al-Garawi, Zahraa, Rodríguez-Alvarez F.J., Zavala-Padilla, Guadalupe, Perez-Carreon, I, Julio, Rodriguez-Ambriz, Sandra L., Herrera, Guillermo A., Becerril-Lujan, Baltazar, Ochoa-Leyva, Adrian, Melendez-Zajgla, Jorge, Serpell, Louise, del Pozo-Yauner, Luis
Publicada:
28 feb 2019
Categoría:
Multidisciplinary
Resumen:
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
beta-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 kappa and lambda 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).
Filiaciones:
Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Delegación Tlalpan, Ciudad de México, 14610, Mexico
School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9QG, United Kingdom
Chemistry Department, College of Science, Mustansiriyah University, Baghdad, Iraq
Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos 62210, Mexico
Centro de Desarrollo de Productos Bióticos, Instituto Politécnico Nacional, Carr. Yautepec-Jojutla Km 6, Calle CEPROBI No. 8, Col. San Isidro, Yautepec, Morelos 62731, Mexico
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, United States
Perez-Carreon, Julio, I , Inst Nacl Med Genom, Perifer Sur 4809, Ciudad De Mexico 14610, Mexico
Univ Sussex, Sch Life Sci, Brighton BN1 9QG, E Sussex, England
Mustansiriyah Univ, Coll Sci, Chem Dept, Baghdad, Iraq
Univ Nacl Autonoma Mexico, Inst Biotecnol, Ave Univ 2001, Cuernavaca 62210, Morelos, Mexico
Inst Politecn Nacl, Ctr Desarrollo Prod Biot, Carr Yautepec Jojutla Km 6,Calle CEPROBI 8, Yautepec 62731, Morelos, Mexico
Louisiana State Univ, Dept Pathol & Translat Pathobiol, Hlth Sci Ctr Shreveport, 1501 Kings Hwy, Shreveport, LA 71103 USA
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