The Aggregation Lab
Selected Publications
Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity. Le Marchand T, et al. Nat Commun. 2018 [PubMed: 29695721]
Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability. Camilloni C, et al. Sci Rep. 2016. [PubMed: 27150430]
Embelin binds to human neuroserpin and impairs its polymerisation. Saga G, et al. Sci Rep. 2016. [PubMed: 26732982]
A covalent homodimer probing early oligomers along amyloid aggregation. Halabelian L, et al. Sci Rep. 2015. [PubMed: 26420657]
Class I Major Histocompatibility Complex, the Trojan Horse for Secretion of Amyloidogenic b2-Microglobulin. Halabelian L, et al. J Biol Chem. 2014. [PubMed: 24338476]
Hereditary systemic amyloidosis due to Asp76Asn variant b2-microglobulin. Valleix S, et al. N Engl J Med. 2012. [PubMed: 22693999]
Current Group
Associate Professor of Biochemistry
stefano.ricagno@unimi.it
Rosaria Russo
Research Technician (Collaborator)
Department of Pathophysiology and Transplantation,
University of Milan
rosaria.russo@unimi.it
Cristina Vinsentin
Postdoctoral Researcher
cristina.visentin@unimi.it
Valentina Speranzini
Postdoctoral Researcher
valentina.speranzini@unimi.it
Luca Broggini
Reseach Assistant (Collaborator)
Institute of Molecular and Translational Cardiology, IRCCS Policlinico San Donato, Milano
luca.broggini@unimi.it
Giulia Rizzi
MS Student
Matteo Giono
MS Research Assistant
Niccolo' Stanghellini
MS Student
Scientific Programmes
Light Chain Amyloidosis
Neuroserpin
Light Chain Amyloidosis
Systemic amyloidoses are protein-misfolding diseases characterized by widespread deposition of amyloid fibrils with severe dysfunction of the affected organs. Light chain (AL) amyloidosis is the most common systemic amyloidosis: fibrils originate from the aggregation of misfolding-prone immunoglobulin light chains (LCs); heart involvement is common and it is the main cause of death. Current therapies for AL amyloidosis are based on suppression of LCs production in the bone marrow by chemotherapy; however, severe heart involvement precludes the use of the most aggressive and most effective schemes.
Solid clinical and experimental evidence, in AL as well as in other amyloidoses, indicates that cell and organ dysfunction is not only due to fibrils, but also to soluble, pre-fibrillar amyloidogenic precursors. In particular, soluble LCs that are cardiotoxic in patients were also shown to be toxicants for cardiac cells and model animals.
However, the molecular features determining the ability of a subset of LCs to target the heart and to be toxic for cardiac cells are still largely undefined. Our aim is to understand the molecular properties determining the toxicity of specific LCs. In order to clarify this issue, we are working on a pool of toxic and non-toxic LCs and we characterise their structure, fold stability, flexibility and hydrophobicity. By site-directed mutagenesis and more in general by protein modification, we aim to pinpoint the toxic species and the biophysical and biochemical properties of LCs, which correlate with the toxicity in patients.
Team:
Martina Maritan, Luca Oberti, Stefano Ricagno
Main collaborators:
Amyloidosis Research and Treatment Centre, University Hospital Pavia (Italy); Molecular Biochemistry and Pharmacology, 'Mario Negri' Institute, Milan (Italy); Dr. A. Barbiroli DeFENS, University of Milan.
Neuroserpin
FENIB (familial encephalopathy with neuroserpin inclusion bodies) is a genetic lethal progressive neurodegenerative condition characterised by severe neurological symptoms. So far, six point mutations of the NS human gene, that lead to NS polymerisation and accumulation within the ER of neurons, have been reported as the cause of FENIB. In their active native state, serpins fold into a common core domain that exposes a long loop, the reactive centre loop (RCL). After protease binding to the RCL and cleavage of the scissile bond, part of the released RCL inserts into b-sheet A of the core domain, dragging the protease still covalently bound to the cleaved RCL causing the protease irreversible inhibition.
The metastability of the serpins native state is also the origin of their propensity to undergo structural transitions towards more stable but inactive states, such as the latent and the polymeric species. The precise structure and elongation mechanism of serpin polymers are still under debate, preventing a rational approach to designing drugs targeting the polymeric species. In fact, to date, all serpinopathies are incurable disorders.
In recent years we have shed light on the structural and biophysical aspects of NS pathological conformers. In particular, we biophysically characterised the NS conformers and provided a model of polymer formation. Recently, we identified embelin (EMB) as the first (and only) low molecular weight compound inhibiting polymer formation and triggering polymer disaggregation in vitro.
The main aims of our research are to better understand the structural and biophysical properties of polymeric NS and to identify small molecules, which are capable to efficiently inhibit NS toxic polymerisation in vitro and in vivo.
Team:
Rosaria Russo, Luca Broggini, Cristina Vinsentin, Elena Codari, Camilla Ornago, Stefano Ricagno
Main Collaborators:
Dr. M. Manno, V. Martorana, R. Noto (IBF Palermo); Dr. E. Miranda Banos (University La Sapienza Rome); Proffs D. Passarella and S. Dalla Valle (University of Milan).
Team:
Benedetta Maria Sala, Luca Broggini, Stefano Ricagno
Main Collaborators:
Prof. V. Bellotti (UCL/University of Pavia); Prof. C. Camilloni and Dr. A. Barbiroli (University of Milan); Proffs R. Grandori and A. Natalello (University of Milan Bicocca); Dr. Guido Pintacuda (Ecole Normale de Lyon); Prof. Annalisa Relini (University of Genoa); Prof. A. Achour (Karolinska Institute, Stockholm).
The Structural Biology Group comprises members from both the DBS-UNIMI and the IBF-CNR. The content herein is not regulated by the University of Milan.