New insights into the metal-induced oxidative degradation pathways of transthyretin

Abstract

Native mass spectrometry reveals a metal-induced oxidation pathway of transthyretin leading to N-terminal backbone fragmentation and oligomer formation.

The Ims Paradox: A Perspective on Structural Ion Mobility‐mass Spectrometry

“…In the case of ligand binding, SID of TTR reveals zinc‐binding (Fig. 19E) while it is obscured in the CID experiment (Poltash et al, 2019). Recent native MS‐SID‐IM‐MS studies on TTR using commercial instruments illustrate the diversity and wealth of information that can be gleaned using SID for topology analysis (Shirzadeh et al, 2019).…”

“…Moreover, changes in structure/stability occur upon Zn(II) binding which might ultimately influence T 4 and/or retinol‐binding. New evidence for metal‐induced oxidation observed using native IM‐MS underscores the importance of rigorous analytical measurements to understand protein behavior ( vide infra ) (Poltash et al, 2019).…”

“…This problem may be mitigated by supplementing the gate at the entrance of the DT with a second gate implemented post‐IM to isolate a single drift time of interest to be transferred for mass analysis; this process is then iterated over the entire drift time window. Alternatively, Fourier transform IM (FT‐IM) uses a linear chirp waveform to modulate both gates by the same pulse which sweeps a user‐defined frequency range over a designated period (Knorr et al, 1985; Morrison, Siems, & Clowers, 2016; Poltash et al, 2018; Poltash et al, 2019). Applying the same pulse pattern to both gates converts the DT into a frequency filter outputting to the orbitrap mass analyzer.…”

“…18B‐b and B‐c). In addition, the high‐resolution ion mobility capability of the FT‐IM‐PF‐DT orbitrap EMR provides evidence for structural perturbation of TTR upon metal‐induced oxidation (Poltash et al, 2019). As shown in Figure 19A, time‐dependent oxidation of TTR can be resolved on EMR indicated by several stepwise mass shifts of 64 Da.…”

“…( E ) SID spectra for M 4+ showing several oxidations on monomeric TTR as well as zinc binding. Reproduced from Poltash et al (2019). ESI, electrospray ionization; SID, surface‐induced dissociation; TTR, transthyretin.…”