Fatal amyloid formation in a patient's antibody light chain is caused by a single point mutation.

ELife
Pamina KazmanJohannes Buchner

Abstract

In systemic light chain amyloidosis, an overexpressed antibody light chain (LC) forms fibrils which deposit in organs and cause their failure. While it is well-established that mutations in the LC's VL domain are important prerequisites, the mechanisms which render a patient LC amyloidogenic are ill-defined. In this study, we performed an in-depth analysis of the factors and mutations responsible for the pathogenic transformation of a patient-derived λ LC, by recombinantly expressing variants in E. coli. We show that proteolytic cleavage of the patient LC resulting in an isolated VL domain is essential for fibril formation. Out of 11 mutations in the patient VL, only one, a leucine to valine mutation, is responsible for fibril formation. It disrupts a hydrophobic network rendering the C-terminal segment of VL more dynamic and decreasing domain stability. Thus, the combination of proteolytic cleavage and the destabilizing mutation trigger conformational changes that turn the LC pathogenic.

References

Oct 1, 1976·Proceedings of the National Academy of Sciences of the United States of America·N Hozumi, S Tonegawa
Dec 9, 1970·Biochemical and Biophysical Research Communications·G G GlennerP Cuatrecasas
Apr 14, 1983·Nature·S Tonegawa
Apr 1, 1980·Proceedings of the National Academy of Sciences of the United States of America·R MakiS Tonegawa
May 1, 1994·Protein Science : a Publication of the Protein Society·L YoungD G Covell
Jun 7, 1994·Proceedings of the National Academy of Sciences of the United States of America·M R HurleR Wetzel
Jan 1, 1997·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·M A Gertz, R A Kyle
Sep 26, 1997·The New England Journal of Medicine·R H FalkM Skinner
Jan 31, 1998·The Journal of Experimental Medicine·P C WilsonV Pascual
Mar 26, 1999·Protein Science : a Publication of the Protein Society·R RaffenF J Stevens
Dec 11, 1999·Nucleic Acids Research·G Johnson, T T Wu
Feb 19, 2000·Journal of Chromatography. B, Biomedical Sciences and Applications·M J Thies, F Pirkl
Aug 9, 2003·The New England Journal of Medicine·Giampaolo Merlini, Vittorio Bellotti
Jan 28, 2004·Cell·David Jung, Frederick W Alt
Feb 10, 2004·Protein Science : a Publication of the Protein Society·Susanne MoelbertChao Tang
Jul 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·A PerrakisV S Lamzin
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Alexei A VaginGarib N Murshudov
Jan 22, 2005·The Journal of Biological Chemistry·Miho KiharaYuji Goto
Apr 27, 2005·Proceedings of the National Academy of Sciences of the United States of America·Gerald P GellermannMarcus Fändrich
Jan 18, 2006·Annual Review of Medicine·Mark B Pepys
Sep 5, 2008·The Journal of Biological Chemistry·Elizabeth M BadenMarina Ramirez-Alvarado
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jun 23, 2009·Current Protein & Peptide Science·Elizabeth M BadenMarina Ramirez-Alvarado
Aug 1, 2009·Haematologica·Giovanni Palladini, Giampaolo Merlini
Aug 4, 2009·Journal of Molecular Biology·Emma Rhiannon SimpsonJohannes Buchner
Sep 23, 2009·The Journal of Pathology·Stina EnqvistPer Westermark
Dec 22, 2009·Trends in Biochemical Sciences·Matthias J FeigeJohannes Buchner
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Nov 17, 2010·Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis·Douglas J Martin, Marina Ramirez-Alvarado
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Jan 18, 2012·Journal of Molecular Biology·Amy R WyattMark R Wilson
Feb 15, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Shaji KumarMorie A Gertz
Jan 24, 2013·Current Topics in Medicinal Chemistry·Marina Ramirez-Alvarado
Nov 16, 2013·Nature Communications·Pavol Skubák, Navraj S Pannu

❮ Previous
Next ❯

Citations

Aug 9, 2020·Zeitschrift für Rheumatologie·K VeelkenN Blank
Jan 28, 2021·Communications Biology·Masahiro NojiYuji Goto
Jan 29, 2021·The Journal of Biological Chemistry·Georg J RottenaicherJohannes Buchner
Feb 10, 2021·Nature Communications·Lynn RadamakerMarcus Fändrich

❮ Previous
Next ❯

Datasets Mentioned

BETA
MK962887

Methods Mentioned

BETA
biopsies
X-ray
PCR
circular dichroism

Software Mentioned

wARP
Amber16
PHASER
Coot
IgBLAST
Crank2
Molprobity
pmemd
XDS
ARP

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.