TY - JOUR
T1 - Identification and characterization of cytotoxic amyloid-like regions in human Pbx-regulating protein-1
AU - Doti, Nunzianna
AU - Monti, Alessandra
AU - Bruckmann, Chiara
AU - Calvanese, Luisa
AU - Smaldone, Giovanni
AU - Caporale, Andrea
AU - Falcigno, Lucia
AU - D'Auria, Gabriella
AU - Blasi, Francesco
AU - Ruvo, Menotti
AU - Vitagliano, Luigi
N1 - Funding Information:
The authors thank Leopoldo Zona for the technical assistance in the NMR experiments and Maurizio Amendola for technical advice and support for mass spectrometry. F.B. thanks AIRC (Grant n 16759 ) and Cariplo Foundation (Grant 2018-0520 ) for financial support. N. D., G. D., L. F., M. R. and L. V. acknowledge the support from Regione Campania for the projects: i) “Fighting Cancer resistance: Multidisciplinary integrated Platform for a technological Innovative Approach to Oncotherapies (Campania Oncotherapies)”; ii) “Development of novel therapeutic approaches for treatment of resistant neoplastic diseases (SATIN)”. C.B. was supported by a Fondazione Umberto Veronesi (FUV) post-doctoral fellowship.
Publisher Copyright:
© 2020 Elsevier B.V.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11/15
Y1 - 2020/11/15
N2 - The ability of many proteins to fold into well-defined structures has been traditionally considered a prerequisite for fulfilling their functions. Protein folding is also regarded as a valuable loophole to escape uncontrolled and harmful aggregations. Here we show that the PBX-regulating protein-1 (PREP1), an important homeodomain transcription factor involved in cell growth and differentiation during embryogenesis, is endowed with an uncommon thermostability. Indeed, circular dichroism analyses indicate that it retains most of its secondary structure at very high temperatures. These findings have important implications for PREP1 functions since it is a stabilizing factor of its partner PBX1. Predictive analyses suggest that the observed PREP1 thermostability could be related to the presence of aggregation-prone regions. Interestingly, synthetic peptides corresponding to these regions exhibit a remarkable propensity to form toxic β-rich amyloid-like aggregates in physiological conditions. On this basis, we suggest that PREP1 stability is an effective way to prevent or limit the formation of harmful aggregates. Notably, one of these PREP1 fragments (residues 117-132) is able to reversibly switch from α-helical to β-rich states depending on the environmental conditions. The chameleon conformational behavior of this peptide makes it an ideal system to study this intriguing and widespread structural transition.
AB - The ability of many proteins to fold into well-defined structures has been traditionally considered a prerequisite for fulfilling their functions. Protein folding is also regarded as a valuable loophole to escape uncontrolled and harmful aggregations. Here we show that the PBX-regulating protein-1 (PREP1), an important homeodomain transcription factor involved in cell growth and differentiation during embryogenesis, is endowed with an uncommon thermostability. Indeed, circular dichroism analyses indicate that it retains most of its secondary structure at very high temperatures. These findings have important implications for PREP1 functions since it is a stabilizing factor of its partner PBX1. Predictive analyses suggest that the observed PREP1 thermostability could be related to the presence of aggregation-prone regions. Interestingly, synthetic peptides corresponding to these regions exhibit a remarkable propensity to form toxic β-rich amyloid-like aggregates in physiological conditions. On this basis, we suggest that PREP1 stability is an effective way to prevent or limit the formation of harmful aggregates. Notably, one of these PREP1 fragments (residues 117-132) is able to reversibly switch from α-helical to β-rich states depending on the environmental conditions. The chameleon conformational behavior of this peptide makes it an ideal system to study this intriguing and widespread structural transition.
KW - NMR
KW - PREP1
KW - Protein aggregation-prone regions (APRs)
KW - Thioflavin-T fluorescence assay
KW - Tumor diagnosis
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U2 - 10.1016/j.ijbiomac.2020.06.271
DO - 10.1016/j.ijbiomac.2020.06.271
M3 - Article
C2 - 32634512
AN - SCOPUS:85087787068
VL - 163
SP - 618
EP - 629
JO - International Journal of Biological Macromolecules
JF - International Journal of Biological Macromolecules
SN - 0141-8130
ER -