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Helix 3 is necessary and sufficient for prion protein’s anti‐Bax function
Author(s) -
LarochePierre Stéphanie,
Jodoin Julie,
LeBlanc Andréa C.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05851.x
Subject(s) - helix (gastropod) , neurodegeneration , function (biology) , bcl 2 associated x protein , biology , microbiology and biotechnology , chemistry , biochemistry , programmed cell death , apoptosis , medicine , caspase 3 , pathology , snail , ecology , disease
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 α‐helix 3 (PrP23–199) or further C‐terminal deletions of α‐helix 1 and 2, and β‐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.