Project Details
Projekt
Conformational dynamics and misfolding of the fibril precursor proteins studied by NMR
Applicant
Professor Dr. Bernd Reif
Subject Area
Structural Biology
Term
from 2019 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 410477202
Systemic AL amyloidosis arises from the misfolding and/or truncation of immunoglobulin light chains and the deposition of amyloid fibrils consisting of light chain fragments, termed AL proteins. In this project we will analyze the structure and the misfolding of the light chains at a residue-specific, if not atom-specific, levels. The detailed aims will be: (i) To characterize with nuclear magnetic resonance the structure and misfolding of full-length light chains. (ii) To characterize with nuclear magnetic resonance the misfolding kinetics of the AL proteins. (iii) To analyse the structure of AL protein aggregates by solid-state nuclear magnetic resonance. Through this work we will test the hypothesis that an extensive restructuring of the protein conformation is necessary to account for the heterogeneity and the localization of the aggregates in patient tissue. We will compare the structural properties of proteins derived from AL patients with proteins derived from multiple myeloma without AL amyloidosis. Through analysis of the interactions between the variable light and the constant light domain we will define as to whether or not these interactions interfere with the further processing of the light chains. Comparison of structures obtained from differing sequences shall enable the derivation of more general principles for AL amyloid fibril formation.
DFG Programme
Research Units
