The Cryo-EM structure of renal amyloid fibrils suggests structurally homogeneous multiorgan aggregation in AL amyloidosis

Immunoglobulin light chain amyloidosis (AL) is caused by the aberrant production of
amyloidogenic light chains (LC) that accumulate as amyloid deposits in vital organs.
Distinct LC sequences in each patient yield distinct amyloid structures. Moreover,
different tissue microenvironments may also cause identical protein precursors to
adopt distinct amyloid structures. These reasons have contributed to the current
popular opinion that amyloid fibrils exhibit structural polymorphism. To address the
impact of the tissue environment on the structural polymorphism of LC fibrils, we
extracted amyloid fibrils from the kidney of an AL patient (AL55) whose cardiac
amyloid structure was previously determined by our group. Here, we show that renal
fibril’s 4.0 Å resolution cryo-electron microscopy (cryo-EM) structure is virtually
identical to one reported for cardiac fibrils. It is the first structural evidence at the
atomic level that LC amyloids, which have been deposited independently in the
different organs of AL patients, remain structurally homogeneous.
Additionally, I will also talk briefly about my previous work on folding pathways of
multidomain and knotted proteins and the impact of post-translational modifications
on the structure-function relationships of deubiquitinase enzymes.


Relevant publications
1. Sarita Puri et al., (2023) The Cryo-EM structure of renal amyloid fibril suggests structurally
homogeneous multiorgan aggregation in AL amyloidosis. (Under review in Communication
2. Sarita Puri and Shang-Te Danny Hsu* (2022) Oxidation of catalytic cysteine of human
deubiquitinase BAP1 triggers misfolding and aggregation in addition to functional loss.
Biochemical and biophysical research communication, 599:57-62.
3. Sarita Puri and Shang-Te Danny Hsu* (2021) Cross-over loop cysteine (C152) acts as an
antioxidant to maintain folding, stability and deubiquitinase activity of UCH-L1 under oxidative
stress. Journal of Molecular Biology, 433(8):166879.
4. Cristina Paissoni, Sarita Puri, Iren Wang, Szu-Yu Chen, Carlo Camilloni* and Shang-Te
Danny Hsu* (2021) Converging experimental and computational views of the knotting
mechanism of the smallest knotted protein. Biophysical Journal, 120(11):2276-86 (First co-
5. Sarita Puri and Chaudhuri, T.K*. (2017) Folding and unfolding pathway of chaperonin GroEL
monomer and elucidation of thermodynamic parameters. International Journal of Biological
Macromolecules, 96:713-726.