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

Stefano Ricagno


Associate Professor of Biochemistry


PubMed, ResearchGate, ORCID, Personal Site

Rosaria Russo


Research Technician (Collaborator)

Department of Pathophysiology and Transplantation,

University of Milan

Cristina Vinsentin


Postdoctoral Researcher


Valentina Speranzini


Postdoctoral Researcher

Luca Broggini


Reseach Assistant (Collaborator)

Institute of Molecular and Translational Cardiology, IRCCS Policlinico San Donato, Milano

Giulia Rizzi


MS Student

Matteo Giono


MS Research Assistant

Niccolo' Stanghellini


MS Student

Scientific Programmes

Light Chain Amyloidosis


β2m and MHC-I

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.




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.






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.



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).

The lab has been working extensively on the molecular bases of the amyloid aggregation propensity of wt and D76N β2m variants. However, many crucial aspects need to be further investigated: the role of fold stability, structural rearrangements and molecular dynamics in determining β2m aggregation. β2m stability and dynamics are being assessed in solution and in crystalline samples. Furthermore the lab is interested in the role of β2m (wt and D76N) and of different peptides MHC-I properties in vitro and in cells. Correlation between MHC-I stability, the half-life of the complex on the cell surface and immunogenicity of different peptides need to be characterised for a deep understanding of the human immune system.
β2m and MHC-I Beta-2 microglobulin (β2m) is the light chain of the major histocompatibility complex Class I (MHC-I). In patients with kidney failure, β2m catabolism is impaired and the protein tends to accumulate in the blood to high concentrations, triggering the formation of amyloid plaques in bones and skeletal joints. Such disorder is known as Dialysis Related Amyloidosis. Moreover a systemic amyloidosis due to a mutated form of Beta-2 microglobulin (Asp76 to Asn) was reported. The D76N variant is very amyloidogenic in vivo and in vitro and can also trigger wt b2m aggregation.


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).



Last update 30/03/22

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.