Heterogeneity in Primary Structure, Post-Translational Modifications, and Germline Gene Usage of Nine Full-Length Amyloidogenic κ1 Immunoglobulin Light Chains
- 16 November 2007
- journal article
- research article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 46 (49) , 14259-14271
- https://doi.org/10.1021/bi7013773
Abstract
Immunoglobulin light chain amyloidosis is a protein misfolding disease in which a monoclonal immunoglobulin (Ig) light chain (LC) with a critically folded β-conformation self-aggregates to form highly ordered, nonbranching amyloid fibrils. The insoluble nature of amyloid fibrils ultimately results in the extracellular deposition of the LC in tissues and organs throughout the body. Structural features that confer amyloidogenic properties on an Ig LC likely include amino acid sequence variations and post-translational modifications, but the specific natures of these changes remain to be defined. As part of an exploration of the effective range of amyloidogenic modifications, this study details the structural and genetic analyses of nine κ1 LC proteins. Urinary LCs were purified by size exclusion chromatography using FPLC, and structural analyses were performed by electrospray ionization, matrix-assisted laser desorption/ionization, and tandem mass spectrometry. RT-PCR amplification, cloning, and sequencing of the monoclonal LC genes were accomplished using bone marrow-derived mRNA. Clinical data were reviewed retrospectively. Characterization of the urinary κ1 LCs revealed extensive post-translational modification in all proteins, in addition to somatic mutations expected on the basis of results from genetic analyses. Post-translational modifications included disulfide-linked dimerization, S-cysteinylation, glycosylation, fragmentation, S-sulfonation, and 3-chlorotyrosine formation. Genetic analyses showed that several LC variable region germline gene donors were represented including O18/O8, O12/O2, L15, and L5. Clinical features included soft tissue, cardiac, renal, and hepatic involvement. This study demonstrated the extensive heterogeneity in primary structure, post-translational modifications, and germline gene usage that occurred in nine amyloidogenic κ1 LC proteins.Keywords
This publication has 58 references indexed in Scilit:
- Soft tissue, joint, and bone manifestations of AL amyloidosis: Clinical presentation, molecular features, and survivalArthritis & Rheumatism, 2007
- A Three-Stage Kinetic Model of Amyloid FibrillationBiophysical Journal, 2007
- Charge differences between in vivo deposits in immunoglobulin light chain amyloidosis and non‐amyloid light chain deposition disease*British Journal of Haematology, 2007
- Nucleation-Dependent Polymerization Is an Essential Component of Amyloid-Mediated Neuronal Cell DeathJournal of Neuroscience, 2005
- Products of Cu(II)-catalyzed oxidation in the presence of hydrogen peroxide of the 1–10, 1–16 fragments of human and mouse β-amyloid peptideJournal of Inorganic Biochemistry, 2004
- Amino acid sequence of a kappa I primary (AL) amyloid protein (AND)Molecular Immunology, 1990
- Relevance of class, molecular weight and isoelectric point in predicting human light chain amyloidogenicityBritish Journal of Haematology, 1990
- The Amino-Acid Sequence of the Variable Region of a Carbohydrate-Containing Amyloid Fibril Protein EPS (Immunoglobulin Light Chain, Type λ)Biological Chemistry Hoppe-Seyler, 1985
- Decarboxylation and transportBioscience Reports, 1982
- Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4Nature, 1970