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Protein conformational perturbations in hereditary amyloidosis : Differential impact of single point mutations in ApoAI amyloidogenic variants

Del Giudice, Rita LU ; Arciello, Angela ; Itri, Francesco ; Merlino, Antonello ; Monti, Maria ; Buonanno, Martina ; Penco, Amanda ; Canetti, Diana ; Petruk, Ganna LU orcid and Monti, Simona Maria , et al. (2016) In Biochimica et Biophysica Acta - General Subjects 1860(2). p.434-444
Abstract

Amyloidoses are devastating diseases characterized by accumulation of misfolded proteins which aggregate in fibrils. Specific gene mutations in Apolipoprotein A I (ApoAI) are associated with systemic amyloidoses. Little is known on the effect of mutations on ApoAI structure and amyloid properties. Here we performed a physicochemical characterization of L75P- and L174S-amyloidogenic ApoAI (AApoAI) variants to shed light on the effects of two single point mutations on protein stability, proteolytic susceptibility and aggregation propensity. Both variants are destabilized in their N-terminal region and generate fibrils with different morphological features. L75PAApoAI is significantly altered in its conformation and compactness, whereas a... (More)

Amyloidoses are devastating diseases characterized by accumulation of misfolded proteins which aggregate in fibrils. Specific gene mutations in Apolipoprotein A I (ApoAI) are associated with systemic amyloidoses. Little is known on the effect of mutations on ApoAI structure and amyloid properties. Here we performed a physicochemical characterization of L75P- and L174S-amyloidogenic ApoAI (AApoAI) variants to shed light on the effects of two single point mutations on protein stability, proteolytic susceptibility and aggregation propensity. Both variants are destabilized in their N-terminal region and generate fibrils with different morphological features. L75PAApoAI is significantly altered in its conformation and compactness, whereas a more flexible and pronounced aggregation-competent state is associated to L174S-AApoAI. These observations point out how single point mutations in ApoAI gene evocate differences in the physico-chemical and conformational behavior of the corresponding protein variants, with the common feature of diverting ApoAI from its natural role towards a pathogenic pathway.

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publishing date
type
Contribution to journal
publication status
published
keywords
Amyloidosis, Apolipoprotein A I, Conformational diseases, Protein stability
in
Biochimica et Biophysica Acta - General Subjects
volume
1860
issue
2
pages
434 - 444
publisher
Elsevier
external identifiers
  • pmid:26515634
  • scopus:84949445171
ISSN
0304-4165
DOI
10.1016/j.bbagen.2015.10.019
language
English
LU publication?
no
additional info
Publisher Copyright: © 2015 Elsevier B.V. All rights reserved.
id
1e1ec3a5-e198-432a-9be9-8158d740ef78
date added to LUP
2025-01-21 15:40:27
date last changed
2025-01-23 03:12:07
@article{1e1ec3a5-e198-432a-9be9-8158d740ef78,
  abstract     = {{<p>Amyloidoses are devastating diseases characterized by accumulation of misfolded proteins which aggregate in fibrils. Specific gene mutations in Apolipoprotein A I (ApoAI) are associated with systemic amyloidoses. Little is known on the effect of mutations on ApoAI structure and amyloid properties. Here we performed a physicochemical characterization of L75P- and L174S-amyloidogenic ApoAI (AApoAI) variants to shed light on the effects of two single point mutations on protein stability, proteolytic susceptibility and aggregation propensity. Both variants are destabilized in their N-terminal region and generate fibrils with different morphological features. L75PAApoAI is significantly altered in its conformation and compactness, whereas a more flexible and pronounced aggregation-competent state is associated to L174S-AApoAI. These observations point out how single point mutations in ApoAI gene evocate differences in the physico-chemical and conformational behavior of the corresponding protein variants, with the common feature of diverting ApoAI from its natural role towards a pathogenic pathway.</p>}},
  author       = {{Del Giudice, Rita and Arciello, Angela and Itri, Francesco and Merlino, Antonello and Monti, Maria and Buonanno, Martina and Penco, Amanda and Canetti, Diana and Petruk, Ganna and Monti, Simona Maria and Relini, Annalisa and Pucci, Piero and Piccoli, Renata and Monti, Daria Maria}},
  issn         = {{0304-4165}},
  keywords     = {{Amyloidosis; Apolipoprotein A I; Conformational diseases; Protein stability}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{2}},
  pages        = {{434--444}},
  publisher    = {{Elsevier}},
  series       = {{Biochimica et Biophysica Acta - General Subjects}},
  title        = {{Protein conformational perturbations in hereditary amyloidosis : Differential impact of single point mutations in ApoAI amyloidogenic variants}},
  url          = {{http://dx.doi.org/10.1016/j.bbagen.2015.10.019}},
  doi          = {{10.1016/j.bbagen.2015.10.019}},
  volume       = {{1860}},
  year         = {{2016}},
}