TY - JOUR
T1 - Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions
AU - Antón , Rosa
AU - Treviño, Miguel
AU - Pantoja-Uceda, David
AU - Félix, Sara
AU - Babu, María
AU - Cabrita, Eurico J.
AU - Zweckstetter, Markus
AU - Tinnefeld, Philip
AU - Vera, Andrés M.
AU - Oroz, Javier
N1 - Funding Information:
This work was supported by the grants PID2019-109276RA-I00 and PID2022-142382OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by FEDER A way to make Europe (to J.O.), and by donations from the Spanish and Mexican Ondine Associations. J.O. was a recipient of a Leonardo Grant from the Spanish BBVA Foundation (BBM_TRA_0203) and is a Ramón y Cajal Fellow of the Spanish AEI-Ministry of Science and Innovation (RYC2018-026042-I funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”). E.C. acknowledges the funding by Fundação para a Ciência e a Tecnologia (FCT-Portugal) of the UCIBIO project (UIDP/04378/2020 and UIDB/04378/2020) and Associate Laboratory Institute for Health and Bioeconomy – i4HB Project (LA/P/0140/2020). S.F. is a PhD student under the PTNMRPhD Program from FCT-Portugal (PD/BD/148028/2019). M.Z. was supported by the European Research Council (ERC) under the EU Horizon 2020 research and innovation programme (grant agreement No. 787679). P.T. acknowledges funding from the Free State of Bavaria through the ONE MUNICH Project Munich Multiscale Biofabrication and A.M.V. is grateful for the support from the Center for NanoScience Munich. N.M.R. experiments were performed in the “Manuel Rico” NMR Laboratory (LMR) of the Spanish National Research Council (CSIC), a node of the Spanish Large-Scale National Facility (ICTS R-LRB). Authors would like to acknowledge Dr. José Manuel Pérez Cañadillas (IQF/CSIC) for providing the TXA fusion plasmid, and for critical reading of the manuscript. Authors acknowledge the use of the Servicio de Microscopía Láser Confocal y Multidimensional in vivo (CIB-CSIC) and Servicio de Proteómica y Genómica (CIB-CSIC).
Funding Information:
This work was supported by the grants PID2019-109276RA-I00 and PID2022-142382OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by FEDER A way to make Europe (to J.O.), and by donations from the Spanish and Mexican Ondine Associations. J.O. was a recipient of a Leonardo Grant from the Spanish BBVA Foundation (BBM_TRA_0203) and is a Ramón y Cajal Fellow of the Spanish AEI-Ministry of Science and Innovation (RYC2018-026042-I funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”). E.C. acknowledges the funding by Fundação para a Ciência e a Tecnologia (FCT-Portugal) of the UCIBIO project (UIDP/04378/2020 and UIDB/04378/2020) and Associate Laboratory Institute for Health and Bioeconomy – i4HB Project (LA/P/0140/2020). S.F. is a PhD student under the PTNMRPhD Program from FCT-Portugal (PD/BD/148028/2019). M.Z. was supported by the European Research Council (ERC) under the EU Horizon 2020 research and innovation programme (grant agreement No. 787679). P.T. acknowledges funding from the Free State of Bavaria through the ONE MUNICH Project Munich Multiscale Biofabrication and A.M.V. is grateful for the support from the Center for NanoScience Munich. N.M.R. experiments were performed in the “Manuel Rico” NMR Laboratory (LMR) of the Spanish National Research Council (CSIC), a node of the Spanish Large-Scale National Facility (ICTS R-LRB). Authors would like to acknowledge Dr. José Manuel Pérez Cañadillas (IQF/CSIC) for providing the TXA fusion plasmid, and for critical reading of the manuscript. Authors acknowledge the use of the Servicio de Microscopía Láser Confocal y Multidimensional in vivo (CIB-CSIC) and Servicio de Proteómica y Genómica (CIB-CSIC).
Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we present the dynamic structure of human PHOX2B C-terminal fragment, which contains the longest polyalanine segment known in mammals. The major α-helical conformation of the polyalanine tract is solely extended by polyalanine expansions in PHOX2B, which are responsible for most congenital central hypoventilation syndrome cases. However, polyalanine expansions in PHOX2B additionally promote nascent homorepeat conformations that trigger length-dependent phase transitions into solid condensates that capture wild-type PHOX2B. Remarkably, HSP70 and HSP90 chaperones specifically seize PHOX2B alternative conformations preventing phase transitions. The precise observation of emerging polymorphs in expanded PHOX2B postulates unbalanced phase transitions as distinct pathophysiological mechanisms in homorepeat expansion diseases, paving the way towards the search of therapeutics modulating biomolecular condensates in central hypoventilation syndrome.
AB - Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we present the dynamic structure of human PHOX2B C-terminal fragment, which contains the longest polyalanine segment known in mammals. The major α-helical conformation of the polyalanine tract is solely extended by polyalanine expansions in PHOX2B, which are responsible for most congenital central hypoventilation syndrome cases. However, polyalanine expansions in PHOX2B additionally promote nascent homorepeat conformations that trigger length-dependent phase transitions into solid condensates that capture wild-type PHOX2B. Remarkably, HSP70 and HSP90 chaperones specifically seize PHOX2B alternative conformations preventing phase transitions. The precise observation of emerging polymorphs in expanded PHOX2B postulates unbalanced phase transitions as distinct pathophysiological mechanisms in homorepeat expansion diseases, paving the way towards the search of therapeutics modulating biomolecular condensates in central hypoventilation syndrome.
UR - http://www.scopus.com/inward/record.url?scp=85186388500&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-46236-5
DO - 10.1038/s41467-024-46236-5
M3 - Article
C2 - 38431667
AN - SCOPUS:85186388500
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1925
ER -
