A model for amyloid fibril formation in immunoglobulin light chains based on comparison of amyloidogenic and benign proteins and specific antibody binding.
In an attempt to understand the mechanism of amyloid fibril formation in light chain amyloidosis, the properties of amyloidogenic (SMA) and benign (LEN) immunoglobulin light chain variable domains (VL) were compared. The conformations of LEN and SMA were measured using secondary and tertiary structural probes over the pH range from 2 and 8. At all pH values, LEN was more stable than SMA. The CD spectra of LEN at pH 2 were comparable to those of SMA at pH 7.5, indicating that the low pH conformation of LEN closely resembles that of SMA at physiological pH. At low pH, a relatively unfolded intermediate conformation is populated for SMA and rapidly leads to amyloid fibrils. The lack of such an intermediate with LEN, is attributed to sequence differences and accounts for the lack of LEN fibrils in the absence of agitation. A kappa IV-specific monoclonal antibody that recognizes the N-terminal of SMA caused unraveling of the fibrils to the protofilaments and was observed to bind to one end of SMA protofilaments by atomic force microscopy. The antibody result indicates that each protofilament is asymmetric with different ends. A model for the formation of fibrils by SMA is proposed.
Khurana
Ritu
R
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.
Souillac
Pierre O
PO
Coats
Alisa C
AC
Minert
Lauren
L
Ionescu-Zanetti
Cristian
C
Carter
Sue A
SA
Solomon
Alan
A
Fink
Anthony L
AL
D000682:Amyloid / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D000686:Amyloidosis / Q000276:immunology / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D001666:Binding Sites, Antibody / Q000276:immunology; D002942:Circular Dichroism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007147:Immunoglobulin Light Chains / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D018625:Microscopy, Atomic Force; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared
D000682:Amyloid; D000911:Antibodies, Monoclonal; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D011994:Recombinant Proteins