The Role of Protein Thermodynamics and Primary Structure in Fibrillogenesis of Variable Domains from Immunoglobulin Light Chains

ABSTRACTSystemic light chain amyloidosis (AL) is a disease caused by overexpression of monoclonal immunoglobulin light chains that form pathogenic amyloid fibrils. These amyloid fibrils deposit in tissues and cause organ failure. Proteins form amyloid fibrils when they partly or fully unfold and expose segments capable of stacking into β-sheets that pair forming a tight, dehydrated interface. These structures, termed steric zippers, constitute the spines of amyloid fibrils. Here, we identify segments within the variable domains of Ig light chains that drive the assembly of amyloid fibrils in AL. We demonstrate there are at least two such segments. Each one can drive amyloid fibril assembly independently of the other. Thus these two segments are therapeutic targets. In addition to elucidating the molecular pathogenesis of AL, these findings also provide an experimental approach to identify segments that drive fibril formation in other amyloid diseases.

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Junctional Diversity in Xenopus tropicalis Immunoglobulin Light Chains

PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS ◽

10.3724/sp.j.1206.2010.00232 ◽

2011 ◽

Vol 37 (11) ◽

pp. 1217-1224

Author(s):

Tong Qin ◽

Li-Ming Ren ◽

Qing-Yong Meng

Keyword(s):

Xenopus Tropicalis ◽

Light Chains ◽

Immunoglobulin Light Chains ◽

Junctional Diversity

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Role of the regulatory light chains in skeletal muscle actomyosin ATPase and in minifilament formation.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)44125-1 ◽

1983 ◽

Vol 258 (21) ◽

pp. 13359-13369 ◽

Cited By ~ 5

Author(s):

S S Margossian ◽

A K Bhan ◽

H S Slayter

Keyword(s):

Skeletal Muscle ◽

Light Chains ◽

Regulatory Light Chains ◽

Actomyosin Atpase

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Human rheumatoid factor crossidiotypes. I. WA and BLA are heat-labile conformational antigens requiring both heavy and light chains.

Journal of Experimental Medicine ◽

10.1084/jem.164.5.1809 ◽

1986 ◽

Vol 164 (5) ◽

pp. 1809-1814 ◽

Cited By ~ 32

Author(s):

V Agnello ◽

J L Barnes

Keyword(s):

Rheumatoid Factor ◽

Primary Structure ◽

Binding Activity ◽

Light Chains ◽

Heat Denaturation ◽

Antigen Binding ◽

Rheumatoid Factors ◽

Simple Method ◽

Heat Labile

Evidence was obtained that both the WA and BLA crossidiotype (XId) groups are conformational antigens requiring both L and H chains and that with heat denaturation the antigens that define the XIds and antigen-binding activity are lost in parallel. In contrast, the primary structure-dependent crossreactive idiotype (CRI), PSL2, which is only weakly detected on native Wa and Bla monoclonal rheumatoid factors (mRFs), became prominently detected on the heated Wa and Bla mRFs. Heat denaturation may provide a simple method for distinguishing Ids determined by conformational antigen from primary structure-dependent Ids. In addition to heat denaturation, some acid conditions commonly used for preparation of RFs were also found to cause marked loss of Id antigen. The finding of PSL2-CRI on Bla mRF indicates that this Id is not unique to the WA XId.

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