PMID- 18578541
OWN - NLM
STAT- MEDLINE
DCOM- 20080903
LR  - 20191210
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Linking)
VI  - 47
IP  - 29
DP  - 2008 Jul 22
TI  - Lipid-derived aldehydes accelerate light chain amyloid and amorphous aggregation.
PG  - 7695-705
LID - 10.1021/bi800333s [doi]
AB  - Antibody light chain (LC) aggregation in vivo leads to the systemic deposition of 
      Ig light chain domains in the form of either amyloid fibrils (AL-amyloidosis) or 
      amorphous deposits, light-chain deposition disease (LCDD), in mainly cardiac or 
      renal tissue and is a pathological condition that is often fatal. Molecular 
      factors that may contribute to the propensity of LCs to aggregate in vivo, such 
      as the protein primary structure or local environment, are intensive areas of 
      study. Herein, we show that the aggregation of a human antibody kappa-(kappa-MJM) 
      and lambda-(lambda-L155) light chain (1 mg/mL) can be accelerated in vitro when 
      they are incubated under physiologically relevant conditions, PBS, pH 7.4 and 37 
      degrees C, in the presence of a panel of biologically relevant lipid-derived 
      aldehydes, 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), glyoxal (GLY), 
      atheronal-A (KA), and atheronal-B (ALD). Thioflavin-T (ThT) and Congo Red (CR) 
      binding assays coupled with turbidity studies reveal that this aldehyde-induced 
      aggregation can be associated with alteration of protein secondary structure to 
      an increased beta-sheet conformation. We observed that the nature of the 
      conformational change is primarily dependent upon the lipidic aldehyde studied, 
      not the protein sequence. Thus, the cholesterol 5,6-secosterols, KA and ALD, 
      cause an amorphous-type aggregation which is ThT and CR negative for both the 
      kappa-MJM and lambda-L155 light chains, whereas 4-HNE, MDA, and GLY induce 
      aggregates that bind both ThT and CR. TEM analysis revealed that amyloid fibrils 
      were formed during the 4-HNE-mediated aggregation of kappa-MJM and lambda-L155 
      light chains, whereas ALD-induced aggregates of these LCs where amorphous in 
      nature. Kinetic profiles of LC aggregation reveal clear differences between the 
      aldehydes, KA and ALD, causing a classic nucleated polymerization-type 
      aggregation, with a lag phase (of approximately 150 h) followed by a growth phase 
      that plateaus, whereas 4-HNE, MDA, and GLY trigger a seeded-type aggregation 
      process that has no lag phase. In-depth studies of the 4-HNE-accelerated 
      aggregation of kappa-MJM and lambda-L155 reveal a clear aldehyde concentration 
      dependence and a process that can be inhibited by the naturally occurring 
      osmolyte trimethylamine N-oxide (TMAO). Given these data, we feel our recently 
      discovered paradigm of inflammatory aldehyde-induced protein misfolding may now 
      extend to LC aggregation.
FAU - Nieva, Jorge
AU  - Nieva J
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
FAU - Shafton, Asher
AU  - Shafton A
FAU - Altobell, Laurence J 3rd
AU  - Altobell LJ 3rd
FAU - Tripuraneni, Sangeetha
AU  - Tripuraneni S
FAU - Rogel, Joseph K
AU  - Rogel JK
FAU - Wentworth, Anita D
AU  - Wentworth AD
FAU - Lerner, Richard A
AU  - Lerner RA
FAU - Wentworth, Paul Jr
AU  - Wentworth P Jr
LA  - eng
GR  - AG028300/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080626
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Aldehydes)
RN  - 0 (Benzothiazoles)
RN  - 0 (Immunoglobulin Light Chains)
RN  - 0 (Lipids)
RN  - 0 (Thiazoles)
RN  - 0 (atheronal-A)
RN  - 0 (atheronal-B)
RN  - 2390-54-7 (thioflavin T)
RN  - 3U05FHG59S (Congo Red)
RN  - 4Y8F71G49Q (Malondialdehyde)
RN  - 50NP6JJ975 (Glyoxal)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - K1CVM13F96 (4-hydroxy-2-nonenal)
SB  - IM
MH  - Aldehydes/*chemistry/pharmacology
MH  - Benzothiazoles
MH  - Cholesterol/analogs & derivatives/chemistry/pharmacology
MH  - Congo Red/chemistry
MH  - Glyoxal/chemistry/pharmacology
MH  - Humans
MH  - Immunoglobulin Light Chains/*chemistry/genetics/metabolism
MH  - Lipids/*chemistry
MH  - Malondialdehyde/chemistry/pharmacology
MH  - Protein Denaturation/drug effects
MH  - Thiazoles/chemistry
EDAT- 2008/06/27 09:00
MHDA- 2008/09/04 09:00
CRDT- 2008/06/27 09:00
PHST- 2008/06/27 09:00 [pubmed]
PHST- 2008/09/04 09:00 [medline]
PHST- 2008/06/27 09:00 [entrez]
AID - 10.1021/bi800333s [doi]
PST - ppublish
SO  - Biochemistry. 2008 Jul 22;47(29):7695-705. doi: 10.1021/bi800333s. Epub 2008 Jun 
      26.