6SM2

Mutant immunoglobulin light chain causing amyloidosis (Pat-1)

Summary for 6SM2

• Entry DOI: 10.2210/pdb6sm2/pdb
• Related: 6SM1
• Descriptor: Pat-1 (2 entities in total)
• Functional Keywords: al amyloidosis, antibody folding, protein stability, dynamics, protein fibril
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 23529.52

Authors

Kazman, P.,Vielberg, M.-T.,Cendales, M.D.P.,Hunziger, L.,Weber, B.,Hegenbart, U.,Zacharias, M.,Koehler, R.,Schoenland, S.,Groll, M.,Buchner, J. (deposition date: 2019-08-21, release date: 2020-03-18, Last modification date: 2024-10-16)

Primary citation

Kazman, P.,Vielberg, M.T.,Pulido Cendales, M.D.,Hunziger, L.,Weber, B.,Hegenbart, U.,Zacharias, M.,Kohler, R.,Schonland, S.,Groll, M.,Buchner, J.
Fatal amyloid formation in a patient's antibody light chain is caused by a single point mutation.
Elife, 9:-, 2020

PubMed 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 V 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 . We show that proteolytic cleavage of the patient LC resulting in an isolated V domain is essential for fibril formation. Out of 11 mutations in the patient V, only one, a leucine to valine mutation, is responsible for fibril formation. It disrupts a hydrophobic network rendering the C-terminal segment of V more dynamic and decreasing domain stability. Thus, the combination of proteolytic cleavage and the destabilizing mutation trigger conformational changes that turn the LC pathogenic.

PubMed: 32151314
DOI: 10.7554/eLife.52300

Experimental method

X-RAY DIFFRACTION (2.5 Å)