5MUH

Crystal structure of an amyloidogenic light chain dimer H7

Summary for 5MUH

• Entry DOI: 10.2210/pdb5muh/pdb
• Descriptor: light chain dimer (2 entities in total)
• Functional Keywords: light chain dimer, light chain amyloidosis, immunoglobulin fold, protein aggregation, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 44695.44

Authors

Oberti, L.,Rognoni, P.,Russo, R.,Maritan, M.,Bacarizo, J.,Bolognesi, M.,Ricagno, S. (deposition date: 2017-01-13, release date: 2017-12-13, Last modification date: 2024-10-23)

Primary citation

Oberti, L.,Rognoni, P.,Barbiroli, A.,Lavatelli, F.,Russo, R.,Maritan, M.,Palladini, G.,Bolognesi, M.,Merlini, G.,Ricagno, S.
Concurrent structural and biophysical traits link with immunoglobulin light chains amyloid propensity.
Sci Rep, 7:16809-16809, 2017

PubMed Abstract: Light chain amyloidosis (AL), the most common systemic amyloidosis, is caused by the overproduction and the aggregation of monoclonal immunoglobulin light chains (LC) in target organs. Due to genetic rearrangement and somatic hypermutation, virtually, each AL patient presents a different amyloidogenic LC. Because of such complexity, the fine molecular determinants of LC aggregation propensity and proteotoxicity are, to date, unclear; significantly, their decoding requires investigating large sets of cases. Aiming to achieve generalizable observations, we systematically characterised a pool of thirteen sequence-diverse full length LCs. Eight amyloidogenic LCs were selected as responsible for severe cardiac symptoms in patients; five non-amyloidogenic LCs were isolated from patients affected by multiple myeloma. Our comprehensive approach (consisting of spectroscopic techniques, limited proteolysis, and X-ray crystallography) shows that low fold stability and high protein dynamics correlate with amyloidogenic LCs, while hydrophobicity, structural rearrangements and nature of the LC dimeric association interface (as observed in seven crystal structures here presented) do not appear to play a significant role in defining amyloid propensity. Based on the structural and biophysical data, our results highlight shared properties driving LC amyloid propensity, and these data will be instrumental for the design of synthetic inhibitors of LC aggregation.

PubMed: 29196671
DOI: 10.1038/s41598-017-16953-7

Experimental method

X-RAY DIFFRACTION (2.65 Å)