Biology subjects

Prokaeva, T.

Publications and source records attributed to Prokaeva, T..

4 recordsLinked to original sources

bioRxiv2026

Cryo-EM reveals patient- versus organ-specific structural diversity and bound ligands in lambda-6 light chain amyloids

Immunoglobulin light chain (LC) amyloidosis is a debilitating multiorgan disease with limited treatment options. Sequence and structural variability make LC amyloids particularly challenging for therapeutic targeting. We report four cryo-EM structures of lambda6-LC amyloid fibrils from four organs of two patients. Fibrils from different patients show different N-terminal conformations expanding known repertoire of lambda6-LC amyloid folds. These folds contain a planar beta-arch with a flexible linker containing the complementarity-determining region 2, flanked by N- and C-terminal segments in variable patient-specific conformations. The surface location of the structurally frustrated charged segment may contribute to the overrepresentation of the lambda6-LC family in amyloidosis. These and other lambda6-LC amyloid structures from different patients show different side chain packing. Conversely, cardiac, renal and splenic amyloids from the same patient exhibit similar structures with small peripheral organ-specific variations. Moreover, they show similar orphan densities, suggesting collagen-like triple helices bound to a tyrosine ladder along the fibril spine. Mass spectrometry detects collagen type-VI in tissue-extracted amyloids. Molecular dynamics simulations suggest amyloid binds collagen-VI triple helices via mixed interactions facilitated by the geometric complementarity between the layered amyloid structure and the triple helix. Similar interactions may drive formation of other amyloid-collagen complexes, influencing biological properties of amyloids.

biophysics↗

bioRxiv2025

Cryo-EM of cardiac AL-224L amyloid reveals shared features in {lambda}6 light chain fibril folds

In amyloid light chain (AL) amyloidosis, aberrant monoclonal antibody light chains (LCs) deposit in vital organs causing organ damage. Each AL patient features a unique LC. Previous cryogenic electron microscopy (cryo-EM) studies revealed different amyloid structures in different AL patients. How LC mutations influence amyloid structures remains unclear. We report a cryo-EM structure of cardiac AL-224L amyloid (2.92 [A] resolution) from {lambda}6-LC family, which is overrepresented in amyloidosis. Comparison with {lambda}6-LC structures from two other patients reveals similarities in amyloid folds. Mutation-induced structural differences in AL-224L include altered C-terminal conformation with an exposed ligand-binding surface; an enlarged hydrophilic pore with orphan density; and altered steric zipper registry with backbone flipping, which likely represent general adaptive mechanisms in amyloids. The results suggest shared features in {lambda}6-LC amyloid folds and reveal how mutation-induced structural changes influence amyloid-ligand interactions in a patient-specific manner.

biophysics↗

bioRxiv2024

An updated AL-Base reveals ranked enrichment of immunoglobulin light chain variable genes in AL amyloidosis

BackgroundEach monoclonal antibody light chain associated with AL amyloidosis has a unique sequence. Defining how these sequences lead to amyloid deposition could facilitate faster diagnosis and lead to new treatments. MethodsLight chain sequences are collected in the Boston University AL-Base repository. Monoclonal sequences from AL amyloidosis, multiple myeloma and the healthy polyclonal immune repertoire were compared to identify differences in precursor gene use, mutation frequency and physicochemical properties. ResultsAL-Base now contains 2,193 monoclonal light chain sequences from plasma cell dyscrasias. Sixteen germline precursor genes were enriched in AL amyloidosis, relative to multiple myeloma and the polyclonal repertoire. Two genes, IGKV1-16 and IGLV1-36, were infrequently observed but highly enriched in AL amyloidosis. The number of mutations varied widely between light chains. AL-associated {kappa} light chains harbored significantly more mutations compared to multiple myeloma and polyclonal sequences, whereas AL-associated {lambda} light chains had fewer mutations. Machine learning tools designed to predict amyloid propensity were less accurate for new sequences than their original training data. ConclusionsRarely-observed light chain variable genes may carry a high risk of AL amyloidosis. New approaches are needed to define sequence-associated risk factors for AL amyloidosis. AL-Base is a foundational resource for such studies.

bioinformatics↗

bioRxiv2024

Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition

BackgroundCardiac dysfunction in AL amyloidosis is thought to be partly related to the direct impact of AL LCs on cardiomyocyte function, with the degree of dysfunction at diagnosis as a major determinant of clinical outcomes. Nonetheless, mechanisms underlying LC-induced myocardial toxicity are not well understood. MethodsWe identified gene expression changes correlating with human cardiac cells exposed to a cardiomyopathy-associated {kappa}AL LC. We then sought to confirm these findings in a clinical dataset by focusing on clinical parameters associated with the pathways dysregulated at the gene expression level. ResultsUpon exposure to a cardiomyopathy-associated {kappa}AL LC, cardiac cells exhibited gene expression changes related to myocardial contractile function and inflammation, leading us to hypothesize that there could be clinically detectable changes in GLS on echocardiogram and serum inflammatory markers in patients. Thus, we identified 29 patients with normal IVSd but abnormal cardiac biomarkers suggestive of LC-induced cardiac dysfunction. These patients display early cardiac biomarker staging, abnormal GLS, and significantly reduced serum inflammatory markers compared to patients with clinically evident amyloid fibril deposition. ConclusionCollectively, our findings highlight early molecular and functional signatures of cardiac AL amyloidosis, with potential impact for developing improved patient biomarkers and novel therapeutics.

cell biology↗