Dr. Chiara Marabelli

Molecular Medicine, University of Pavia, Pavia, Italy

Dr. Chiara Marabelli

Molecular Medicine, University of Pavia, Pavia, Italy

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Academic Career Length

11Years (2016-Present)

(Calculated once Scilit publication data is synced: current year − year of first publication + 1)

Representative Publications

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28 July 2024 in Nature Communications

Journal Article

Helical superstructures between amyloid and collagen in cardiac fibrils from a patient with AL amyloidosis

Tim Schulte

Antonio Chaves-Sanjuan

Valentina Speranzini

Kevin Sicking

Melissa Milazzo

Stefano Ricagno

+15

Systemic light chain (LC) amyloidosis (AL) is a disease where organs are damaged by an overload of a misfolded patient-specific antibody-derived LC, secreted by an abnormal B cell clone. The high LC concentration in the blood leads to amyloid deposition at organ sites. Indeed, cryogenic electron microscopy (cryo-EM) has revealed unique amyloid folds for heart-derived fibrils taken from different patients. Here, we present the cryo-EM structure of heart-derived AL amyloid (AL59) from another patient with severe cardiac involvement. The double-layered structure displays a u-shaped core that is closed by a β-arc lid and extended by a straight tail. Noteworthy, the fibril harbours an extended constant domain fragment, thus ruling out the variable domain as sole amyloid building block. Surprisingly, the fibrils were abundantly concatenated with a proteinaceous polymer, here identified as collagen VI (COLVI) by immuno-electron microscopy (IEM) and mass-spectrometry. Cryogenic electron tomography (cryo-ET) showed how COLVI wraps around the amyloid forming a helical superstructure, likely stabilizing and protecting the fibrils from clearance. Thus, here we report structural evidence of interactions between amyloid and collagen, potentially signifying a distinct pathophysiological mechanism of amyloid deposits.

1 December 2016 in Current Opinion in Structural Biology

Journal Article

The growing structural and functional complexity of the LSD1/KDM1A histone demethylase

Chiara Marabelli

Biagina Marrocco

Andrea Mattevi

1 April 2019 in Cell Reports

Journal Article

A Tail-Based Mechanism Drives Nucleosome Demethylation by the LSD2/NPAC Multimeric Complex

Biagina Marrocco

Sarah Picaud

LSD1 and LSD2 are homologous histone demethylases with opposite biological outcomes related to chromatin silencing and transcription elongation, respectively. Unlike LSD1, LSD2 nucleosome-demethylase activity relies on a specific linker peptide from the multidomain protein NPAC. We used single-particle cryoelectron microscopy (cryo-EM), in combination with kinetic and mutational analysis, to analyze the mechanisms underlying the function of the human LSD2/NPAC-linker/nucleosome complex. Weak interactions between LSD2 and DNA enable multiple binding modes for the association of the demethylase to the nucleosome. The demethylase thereby captures mono- and dimethyl Lys4 of the H3 tail to afford histone demethylation. Our studies also establish that the dehydrogenase domain of NPAC serves as a catalytically inert oligomerization module. While LSD1/CoREST forms a nucleosome docking platform at silenced gene promoters, LSD2/NPAC is a multifunctional enzyme complex with flexible linkers, tailored for rapid chromatin modification, in conjunction with the advance of the RNA polymerase on actively transcribed genes.

19 April 2016 in Human Molecular Genetics

Journal Article

LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors

Emanuela Toffolo

Genetic diseases often lead to rare and severe syndromes and the identification of the genetic and protein alterations responsible for the pathogenesis is essential to understand both the physiological and pathological role of the gene product. Recently, de novo variants have been mapped on the gene encoding for the histone demethylase LSD1/KDM1A in three patients characterized by a new genetic disorder. We have analyzed the effects of these pathological mutations on the structure, stability, and activity of LSD1 using both in vitro and cellular approaches. The three mutations (Glu403Lys, Asp580Gly and Tyr785His) affect active-site residues and lead to a partial impairment of catalytic activity. They also differentially perturb the ability of LSD1 to engage transcription factors that orchestrate key developmental programs. Moreover, cellular data clearly demonstrate a decrease in the protein cellular half-life. Taken together, these results demonstrate the relevance of LSD1 in gene regulation and how even moderate alterations in its stability, catalytic activity, and binding properties can strongly affect organism development. This depicts a perturbed interplay of catalytic and non-catalytic processes at the origin of the pathology.

13 August 2019 in Journal of Chemical Information and Modeling

Journal Article

Impact of Mutations on NPAC Structural Dynamics: Mechanistic Insights from MD Simulations

Simona Pilotto

Elisabetta Moroni

23 November 2023 in Biomolecules

Journal Article

The Structural–Functional Crosstalk of the Calsequestrin System: Insights and Pathological Implications

Chiara Marabelli

Demetrio Julian Santiago

Silvia G. Priori

Calsequestrin (CASQ) is a key intra-sarcoplasmic reticulum Ca²⁺-handling protein that plays a pivotal role in the contraction of cardiac and skeletal muscles. Its Ca²⁺-dependent polymerization dynamics shape the translation of electric excitation signals to the Ca²⁺-induced contraction of the actin-myosin architecture. Mutations in CASQ are linked to life-threatening pathological conditions, including tubular aggregate myopathy, malignant hyperthermia, and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The variability in the penetrance of these phenotypes and the lack of a clear understanding of the disease mechanisms associated with CASQ mutations pose a major challenge to the development of effective therapeutic strategies. In vitro studies have mainly focused on the polymerization and Ca²⁺-buffering properties of CASQ but have provided little insight into the complex interplay of structural and functional changes that underlie disease. In this review, the biochemical and structural natures of CASQ are explored in-depth, while emphasizing their direct and indirect consequences for muscle Ca²⁺ physiology. We propose a novel functional classification of CASQ pathological missense mutations based on the structural stability of the monomer, dimer, or linear polymer conformation. We also highlight emerging similarities between polymeric CASQ and polyelectrolyte systems, emphasizing the potential for the use of this paradigm to guide further research.

About Me

Chiara Marabelli is a postdoctoral researcher focusing on the crossroad between the biochemistry and biophysics of proteins involved in the Excitation–Contraction Coupling in cardiac physiology and disease. After obtaining her Bachelor Degree in Biotechnology in 2013, and her Master's Degree in Molecular Biology and Genetics in 2015, she started her Doctorate Degree at the Biocrystallography group led by Prof. Andrea Mattevi. Her project led her to solve the Cryo-EM structure(s) of a chromatin remodeller in complex with its nucleosome structure in collaboration with Prof. Sriram Subramaniam. The successful experimental strategy undertaken for an otherwise non-stabile complex was the result of an inter-disciplinary work between chemists and biologists. She broadened her inter-disciplinary skills in the frame of an industrial partnership for the engineering of enzymes as selective biocatalysts for the production of vanillin and bioplastic monomers from pulp fraction. In 2019, she moved to the Cryo-EM Facility at the University of Milan, Italy, led by Prof. Martino Bolognesi, where she assisted with or collaborated on more than 15 projects regarding enzymes and nucleo-protein complexes, membrane channels, ex vivo and synthetic amyloids, and nanoparticles for pharmaceutical use. After her time as an EM Specialist at the Human technophile research centre, Milan, Italy, she moved, in 2022, to the Molecular Cardiology laboratory led by Professor Silvia G. Priori in Pavia, Italy.

Dr. Chiara Marabelli

Dr. Chiara Marabelli

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