ScieNtific RePORtS | 7: 16809 | DOI:10.1038/s41598-017-16953-7
Concurrent structural and
biophysical traits link with
immunoglobulin light chains
, Paola Rognoni
, Alberto Barbiroli
, Francesca Lavatelli
, Rosaria Russo
, Giovanni Palladini
, Martino Bolognesi
, Giampaolo Merlini
Light chain amyloidosis (AL), the most common systemic amyloidosis, is caused by the overproduction
and the aggregation of monoclonal immunoglobulin light chains (LC) in target organs. Due to
genetic rearrangement and somatic hypermutation, virtually, each AL patient presents a dierent
amyloidogenic LC. Because of such complexity, the ne molecular determinants of LC aggregation
propensity and proteotoxicity are, to date, unclear; signicantly, their decoding requires investigating
large sets of cases. Aiming to achieve generalizable observations, we systematically characterised a
pool of thirteen sequence-diverse full length LCs. Eight amyloidogenic LCs were selected as responsible
for severe cardiac symptoms in patients; ve non-amyloidogenic LCs were isolated from patients
aected by multiple myeloma. Our comprehensive approach (consisting of spectroscopic techniques,
limited proteolysis, and X-ray crystallography) shows that low fold stability and high protein dynamics
correlate with amyloidogenic LCs, while hydrophobicity, structural rearrangements and nature of
the LC dimeric association interface (as observed in seven crystal structures here presented) do not
appear to play a signicant role in dening amyloid propensity. Based on the structural and biophysical
data, our results highlight shared properties driving LC amyloid propensity, and these data will be
instrumental for the design of synthetic inhibitors of LC aggregation.
Systemic amyloidoses are protein misfolding diseases caused by deposition of proteins as brillar aggregates in
. In these disorders, the amyloidogenic protein precursor is produced at sites distant from those
of deposition, being then transported to the tissues through blood
. Light chain amyloidosis (AL) is the most
frequent systemic form, with an incidence of approximately 10 cases per million-persons/year; it is caused by dep-
osition of excess monoclonal immunoglobulin light chains (LCs) produced by a bone marrow plasma cell clone
Since the incidence of AL increases with age, the socio-economic impact of this devastating disease is expected to
grow within the ageing population of industrialized countries.
AL is a heterogeneous disease, both in terms of causative proteins and of the pattern of organ involvement.
e extreme variability among LCs, caused by genetic rearrangement and somatic hypermutation
, translates into
the fact that virtually every monoclonal LC is unique in its amino acid sequence. e clinical phenotype of AL is
also polymorphic, most patients showing multi-organ involvement at presentation
: involvement of the heart, in
particular, is frequent (~75% of cases) and dictates the prognosis
. A growing body of experimental and clinical
evidences from patients with cardiac involvement indicate that damage is not only caused by bril deposits, but
also by pre-brillar amyloidogenic LCs, which are themselves directly toxic for target cells
Understanding the specic properties of dierent LCs in their soluble native state, therefore, appears as a
rational approach to explore the determinants of amyloid formation, organ tropism and dysfunction in vivo.
Dipartimento di Bioscienze, Università degli Studi di Milano, 20133, Milano, Italy.
Amyloidosis Research and
Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University
of Pavia, 27100, Pavia, Italy.
Dipartimento di Scienze per gli Alimenti, la Nutrizione e l’Ambiente, Università degli
Studi di Milano, 20133, Milano, Italy.
Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università
degli Studi di Milano, Milano, Italy.
CNR Istituto di Biosica, c/o Università degli Studi di Milano, 20133, Milano, Italy.
Correspondence and requests for materials should be addressed to S.R. (email: Stefano.firstname.lastname@example.org)
Received: 10 May 2017
Accepted: 10 November 2017
Published: xx xx xxxx