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@ARTICLE{SternkeHoffmann:1016953,
      author       = {Sternke-Hoffmann, Rebecca and Pauly, Thomas and Norrild,
                      Rasmus K. and Hansen, Jan and Tucholski, Florian and Høie,
                      Magnus Haraldson and Marcatili, Paolo and Dupré, Mathieu
                      and Duchateau, Magalie and Rey, Martial and Malosse,
                      Christian and Metzger, Sabine and Boquoi, Amelie and
                      Platten, Florian and Egelhaaf, Stefan U. and Chamot-Rooke,
                      Julia and Fenk, Roland and Nagel-Steger, Luitgard and Haas,
                      Rainer and Buell, Alexander K.},
      title        = {{W}idespread amyloidogenicity potential of multiple myeloma
                      patient-derived immunoglobulin light chains},
      journal      = {BMC biology},
      volume       = {21},
      number       = {1},
      issn         = {1741-7007},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {FZJ-2023-03861},
      pages        = {21},
      year         = {2023},
      abstract     = {Background:In a range of human disorders such as multiple
                      myeloma (MM), immunoglobulin light chains (IgLCs) can be
                      produced at very high concentrations. This can lead to
                      pathological aggregation and deposition of IgLCs in
                      different tissues, which in turn leads to severe and
                      potentially fatal organ damage. However, IgLCs can also be
                      highly soluble and non-toxic. It is generally thought that
                      the cause for this differential solubility behaviour is
                      solely found within the IgLC amino acid sequences, and a
                      variety of individual sequence-related biophysical
                      properties (e.g. thermal stability, dimerisation) have been
                      proposed in different studies as major determinants of the
                      aggregation in vivo. Here, we investigate biophysical
                      properties underlying IgLC amyloidogenicity.Results:We
                      introduce a novel and systematic workflow, Thermodynamic and
                      Aggregation Fingerprinting (ThAgg-Fip), for detailed
                      biophysical characterisation, and apply it to nine different
                      MM patient-derived IgLCs. Our set of pathogenic IgLCs spans
                      the entire range of values in those parameters previously
                      proposed to define in vivo amyloidogenicity; however, none
                      actually forms amyloid in patients. Even more surprisingly,
                      we were able to show that all our IgLCs are able to form
                      amyloid fibrils readily in vitro under the influence of
                      proteolytic cleavage by co-purified
                      cathepsins.Conclusions:We show that (I) in vivo aggregation
                      behaviour is unlikely to be mechanistically linked to any
                      single biophysical or biochemical parameter and (II)
                      amyloidogenic potential is widespread in IgLC sequences and
                      is not confined to those sequences that form amyloid fibrils
                      in patients. Our findings suggest that protein sequence,
                      environmental conditions and presence and action of
                      proteases all determine the ability of light chains to form
                      amyloid fibrils in patients.},
      cin          = {IBI-7 / IBI-4},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-7-20200312 / I:(DE-Juel1)IBI-4-20200312},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)36 / PUB:(DE-HGF)16},
      pubmed       = {36737754},
      UT           = {WOS:000940546800003},
      doi          = {10.1186/s12915-022-01506-w},
      url          = {https://juser.fz-juelich.de/record/1016953},
}