Journal ArticleDOI
Four structural risk factors identify most fibril-forming kappa light chains
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TLDR
It is suggested that it is feasible to predict fibril propensity by analysis of primary structure of antibody LCs, and this study focuses on amyloidogenesis within the Kl family of human LCs.Abstract:
Antibody light chains (LCs) comprise the most structurally diverse family of proteins involved in amyloidosis. Many antibody LCs incorporate structural features that impair their stability and solubility, leading to their assembly into fibrils and to their subsequent pathological deposition when produced in excess during multiple myeloma and primary amyloidosis. The particular amino acid variations in antibody LCs that account for fibril formation and amyloidogenesis have not been identified. This study focuses on amyloidogenesis within the kappa1 family of human LCs. Reanalysis of the current database of primary structures of proteins from more than 100 patients who produced kappa1 LCs, 37 of which were amyloidogenic, reveals apparent structural features that may contribute to amyloidosis. These features include loss of conserved residues or the gain of particular residues through mutation at sites involving a repertoire of approximately 20% of the amino acid positions in the light chain variable domain (V(L)). Moreover 80% of all kappa1 amyloidogenic V(L)s are identifiable by the presence of at least one of three single-site substitutions or the acquisition of an N-linked glycosylation site through mutations. These findings suggest that it is feasible to predict fibril propensity by analysis of primary structure.read more
Citations
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Journal ArticleDOI
Molecular mechanisms of amyloidosis.
TL;DR: The molecular basis of various types of amyloidosis is reviewed and new ways of treating these disorders are proposed.
Journal ArticleDOI
Biophysical properties of human antibody variable domains
TL;DR: Possibility for further improvement of the biophysical properties of individual frameworks are suggested and recommendations for library design are given.
Journal ArticleDOI
Clinical aspects of systemic amyloid diseases.
TL;DR: The most effective approach to treatment of the systemic amyloidsoses involves shutting down, or substantially reducing the synthesis of the amyloid precursor, or, as in the case of beta(2)-microglobulin, promoting its clearance.
Journal ArticleDOI
The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell burden.
Raymond L. Comenzo,Yana Zhang,Yana Zhang,Carmen Martinez,Carmen Martinez,Keren Osman,Keren Osman,Guillermo A. Herrera,Guillermo A. Herrera +8 more
TL;DR: In the in vitro model, unlike all other AL light chains tested, lambdaVI light chains formed amyloids rapidly both with and without amyloid-enhancing factor, supporting the hypothesis that germ line gene use and plasma cell burden influence the organ tropism of AL.
Journal ArticleDOI
The pathogenesis and diagnosis of acute kidney injury in multiple myeloma
Colin A. Hutchison,Vecihi Batuman,Judith Behrens,Frank Bridoux,Christophe Sirac,Angela Dispenzieri,Guillermo A. Herrera,Helen J. Lachmann,Paul W. Sanders +8 more
TL;DR: The mechanisms of disease and diagnostic approaches to patients with acute kidney injury complicating multiple myeloma are discussed.
References
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Journal ArticleDOI
Protein misfolding, evolution and disease
TL;DR: This paper is a contribution from the Oxford Centre for Molecular Sciences, which is funded by the BBSRC, EPSRC and MRC.
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Designing conditions for in vitro formation of amyloid protofilaments and fibrils
Fabrizio Chiti,Paul Webster,Niccolò Taddei,Anne Clark,Massimo Stefani,Giampietro Ramponi,Christopher M. Dobson +6 more
TL;DR: The results indicate that formation of amyloid occurs when the native fold of a protein is destabilized under conditions in which noncovalent interactions, and in particular hydrogen bonding, within the polypeptide chain remain favorable.
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Amyloid fibril formation by an SH3 domain
TL;DR: Results indicate that the A state of PI3-SH3 is partially folded and support the hypothesis that partially folded states formed in solution are precursors of amyloid deposition.
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A role for destabilizing amino acid replacements in light-chain amyloidosis
TL;DR: The results are consistent with a mechanism for the disease process in which the VL domain, either before or after proteolytic cleavage from the L-chain constant region domain, unfolds by virtue of one or more destabilizing amino acid replacements to generate an aggregation-prone nonnative state.
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Monoclonal Immunoglobulin Deposition Disease: Light Chain and Light and Heavy Chain Deposition Diseases and Their Relation to Light Chain Amyloidosis: Clinical Features, Immunopathology, and Molecular Analysis
TL;DR: The nonamyloid forms were found in 13 patients who had evidence of plasmacytic dyscrasia by the immunohistochemical detection of immunoglobulin light chains of kappa or lambda class and by the absence ofAmyloid P component in tissue sections that did not show the birefringence characteristic of amyloid after Congo Red staining.