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PDBsum entry 1pw3
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Immune system
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PDB id
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1pw3
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural basis of light chain amyloidogenicity: comparison of the thermodynamic properties, Fibrillogenic potential and tertiary structural features of four vlambda6 proteins.
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Authors
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J.S.Wall,
V.Gupta,
M.Wilkerson,
M.Schell,
R.Loris,
P.Adams,
A.Solomon,
F.Stevens,
C.Dealwis.
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Ref.
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J Mol Recognit, 2004,
17,
323-331.
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PubMed id
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Abstract
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Primary (AL) amyloidosis results from the pathologic deposition of monoclonal
light chains as amyloid fibrils. Studies of recombinant-derived variable region
(VL) fragments of these proteins have shown an inverse relationship between
thermodynamic stability and fibrillogenic potential. Further, ionic interactions
within the VL domain were predicted to influence the kinetics of light chain
fibrillogenicity, as evidenced from our analyses of a relatively stable Vlambda6
protein (Jto) with a long range electrostatic interaction between Asp and Arg
side chains at position 29 and 68, respectively, and an unstable, highly
fibrillogenic Vlambda6 protein (Wil) that had neutral amino acids at these
locations. To test this hypothesis, we have generated two Jto-related mutants
designed to disrupt the interaction between Asp 29 and Arg 68 (JtoD29A and
JtoR68S). Although the thermodynamic stabilities of unfolding for these two
molecules were identical, they exhibited very different kinetics of fibril
formation: the rate of JtoD29A fibrillogenesis was slow and comparable to the
parent molecule, whereas that of JtoR68S was significantly faster.
High-resolution X-ray diffraction analyses of crystals prepared from the two
mutants having the same space group and unit cell dimensions revealed no
significant main-chain conformational changes. However, several notable
side-chain alterations were observed in JtoR68S, as compared with JtoD29A, that
resulted in the solvent exposure of a greater hydrophobic surface and
modifications in the electrostatic potential surface. We posit that these
differences contributed to the enhanced fibrillogenic potential of the Arg 68
mutant, since both Jto mutants lacked the intrachain ionic interaction and were
equivalently unstable. The information gleaned from our studies has provided
insight into structural parameters that in addition to overall thermodynamic
stability, contribute to the fibril forming propensity of immunoglobulin light
chains.
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