5IR3

Crystal structure of the recombinant highest fibrillogenic natural mutant (obtained from patient AR) derived from lambda 6 light chain variable domain

Summary for 5IR3

• Entry DOI: 10.2210/pdb5ir3/pdb
• Related: 2W0K 3B5G 3BDX 5C9K
• Descriptor: Ig lambda chain V-VI region AR, ACETATE ION (3 entities in total)
• Functional Keywords: beta-sandwich, immunoglobulin, al amyloidosis, immune system
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted : P01721
• Total number of polymer chains: 1
• Total formula weight: 11985.86

Authors

Hernandez-Santoyo, A.,Rodriguez-Romero, A. (deposition date: 2016-03-11, release date: 2017-06-14, Last modification date: 2024-11-06)

Primary citation

Luna-Martinez, O.D.,Hernandez-Santoyo, A.,Villalba-Velazquez, M.I.,Sanchez-Alcala, R.,Fernandez-Velasco, D.A.,Becerril, B.
Stabilizing an amyloidogenic lambda 6 light chain variable domain.
FEBS J., 284:3702-3717, 2017

PubMed Abstract: Light chain amyloidosis is a lethal disease where vital organs are damaged by the fibrillar aggregation of monoclonal light chains. λ6a is an immunoglobulin light chain encoded by the germ-line gene segment implicated in this disease. AR is a patient-derived germ-line variant with a markedly low thermodynamic stability and prone to form fibrils in vitro in less than an hour. Here, we sought to stabilize this domain by mutating some residues back to the germ-line sequence, and the most stabilizing mutations were the single-mutant AR-F21I and the double-mutant AR-F21/IV104L, both located in the hydrophobic core. While mutation Arg25Gly in 6aJL2 destabilized the domain, mutating Gly25 back to arginine in AR did not contribute to stabilization as expected. Crystallographic structures of AR and 6a-R25G were generated to explain this discrepancy. Finally, 6a-R25G crystals revealed an octameric assembly which was emulated into 6aJL2 and AR crystals by replicating their structural parameters and suggesting a common assembly pattern.

PubMed: 28898537
DOI: 10.1111/febs.14265

Experimental method

X-RAY DIFFRACTION (1.7 Å)