Helix 3 is necessary and sufficient for prion protein's anti-Bax function.
J Neurochem
; 108(4): 1019-31, 2009 Feb.
Article
em En
| MEDLINE
| ID: mdl-19196429
ABSTRACT
To identify the structural elements of the prion protein (PrP) necessary for its protective function against Bcl-2 associated protein X (Bax), we performed structure-function analyses of the anti-Bax function of cytosolic PrP (CyPrP) in MCF-7 cells. Deletions of 1, 2, or 3 N-terminal Bcl-2 homology domain 2-like octapeptide repeats (BORs), but not deletion of all four BORs, abolish CyPrPs anti-Bax function. Deletion of alpha-helix 3 (PrP23-199) or further C-terminal deletions of alpha-helix 1 and 2, and beta-strand 1 and 2 (PrP23-172, PrP23-160, PrP23-143, and PrP23-127) eliminates CyPrPs protection against Bax-mediated cell death. The substitution of helix 3 amino acid residues K204, V210, and E219 by proline inhibits the anti-Bax function of CyPrP. The substitution of K204, but not V210 and E219, by alanine residues also prevents CyPrPs anti-Bax function. Expression of PrPs helix 3 displays anti-Bax activity in MCF-7 cells and in human neurons. Together, these results indicate that although the BOR domain has an influence on PrPs anti-Bax function, the helix 3 is necessary and sufficient for the anti-Bax function of CyPrP. Identification of helix 3 as the structural element for the anti-Bax function thus provides a molecular target to modulate PrPs anti-Bax function in cancer and neurodegeneration.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Apoptose
/
Proteínas PrPC
/
Proteína X Associada a bcl-2
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article