8P7G

Structural characterization of PHOX2B and its DNA interactions shed lights into the molecular basis of the + 7Ala variant pathogenicity in CCHS

Summary for 8P7G

• Entry DOI: 10.2210/pdb8p7g/pdb
• NMR Information: BMRB: 34822
• Descriptor: Paired mesoderm homeobox protein 2B (1 entity in total)
• Functional Keywords: transcription factor, homeodomain, congenital central hypoventilation syndrome, polyala expansions, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 7741.80

Authors

Russo, L.,Diana, D.,Fattorusso, R. (deposition date: 2023-05-30, release date: 2024-05-15, Last modification date: 2024-06-26)

Primary citation

Diana, D.,Pirone, L.,Russo, L.,D'Abrosca, G.,Madheswaran, M.,Benfante, R.,Di Lascio, S.,Caldinelli, L.,Fornasari, D.,Acconcia, C.,Corvino, A.,Ventserova, N.,Pollegioni, L.,Isernia, C.,Di Gaetano, S.,Malgieri, G.,Pedone, E.M.,Fattorusso, R.
Structural characterization of PHOX2B and its DNA interaction shed light on the molecular basis of the +7Ala variant pathogenicity in CCHS.
Chem Sci, 15:8858-8872, 2024

PubMed Abstract: An expansion of poly-alanine up to +13 residues in the C-terminus of the transcription factor PHOX2B underlies the onset of congenital central hypoventilation syndrome (CCHS). Recent studies demonstrated that the alanine tract expansion influences PHOX2B folding and activity. Therefore, structural information on PHOX2B is an important target for obtaining clues to elucidate the insurgence of the alanine expansion-related syndrome and also for defining a viable therapy. Here we report by NMR spectroscopy the structural characterization of the homeodomain (HD) of PHOX2B and HD + C-terminus PHOX2B protein, free and in the presence of the target DNA. The obtained structural data are then exploited to obtain a structural model of the PHOX2B-DNA interaction. In addition, the variant +7Ala, responsible for one of the most frequent forms of the syndrome, was analysed, showing different conformational proprieties in solution and a strong propensity to aggregation. Our data suggest that the elongated poly-alanine tract would be related to disease onset through a loss-of-function mechanism. Overall, this study paves the way for the future rational design of therapeutic drugs, suggesting as a possible therapeutic route the use of specific anti-aggregating molecules capable of preventing variant aggregation and possibly restoring the DNA-binding activity of PHOX2B.

PubMed: 38873078
DOI: 10.1039/d3sc06427a

Experimental method

SOLUTION NMR