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Pore-forming activity of BAD is regulated by specific phosphorylation and structural transitions of the C-terminal part

Title data

Polzien, Lisa ; Baljuls, Angela ; Roth, Heide-Marie ; Kuper, Jochen ; Benz, Roland ; Schweimer, Kristian ; Hekman, Mirko ; Rapp, Ulf R.:
Pore-forming activity of BAD is regulated by specific phosphorylation and structural transitions of the C-terminal part.
In: Biochimica et Biophysica Acta : General Subjects. Vol. 1810 (2011) Issue 2 . - pp. 162-169.
ISSN 1872-8006
DOI: https://doi.org/10.1016/j.bbagen.2010.11.002

Abstract in another language

BACKGROUND: BAD protein (Bcl-2 antagonist of cell death) belongs to the BH3-only subfamily of proapoptotic proteins and is proposed to function as the sentinel of the cellular health status. Physiological activity of BAD is regulated by phosphorylation, association with 14-3-3 proteins, binding to membrane lipids and pore-formation. Since the functional role of the BAD C-terminal part has not been considered so far, we have investigated here the interplay of the structure and function of this region.
METHODS: The structure of the regulatory C-terminal part of human BAD was analyzed by CD spectroscopy. The channel forming activity of full-length BAD and BAD peptides was carried out by lipid bilayer measurements. Interactions between proteins and peptides were monitored by the surface plasmon resonance technique.
RESULTS: In aqueous solution, C-terminal part of BAD exhibits a well-ordered structure and stable conformation. In a lipid environment, the helical propensity considerably increases. The interaction of the C-terminal segment of BAD with the isolated BH3 domain results in the formation of permanently open pores whereby the phosphorylation of serine 118 within the BH3 domain is necessary for effective pore-formation. In contrast, phosphorylation of serine 99 in combination with 14-3-3 association suppresses formation of channels.
CONCLUSIONS: C-terminal part of BAD controls BAD function by structural transitions, lipid binding and phosphorylation. Conformational changes of this region upon membrane interaction in conjunction with phosphorylation of the BH3 domain suggest a novel mechanism for regulation of BAD.
GENERAL SIGNIFICANCE: Multiple signaling pathways mediate inhibition and activation of cell death via BAD.s proposed to function as the sentinel of the cellular health status. Physiological activity of BAD is regulated by phosphorylation, association with 14-3-3 proteins, binding to membrane lipids and pore-formation. Since the functional role of the BAD C-terminal part has not been considered so far, we have investigated here the interplay of the structure and function of this region.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Former Professors
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biopolymers
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Former Professors > Chair Biopolymers - Univ.-Prof. Dr. Paul Rösch
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biopolymers > Lehrstuhl Biopolymere - Apl. Prof. Dr. Birgitta Wöhrl
Result of work at the UBT: Yes
DDC Subjects: 500 Science
500 Science > 500 Natural sciences
500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 15 Jan 2015 09:26
Last Modified: 11 Jun 2019 08:56
URI: https://eref.uni-bayreuth.de/id/eprint/5566