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

Titelangaben

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. Bd. 1810 (2011) Heft 2 . - S. 162-169.
ISSN 1872-8006
DOI: https://doi.org/10.1016/j.bbagen.2010.11.002

Abstract

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.

Weitere Angaben

Publikationsform: Artikel in einer Zeitschrift
Begutachteter Beitrag: Ja
Institutionen der Universität: Fakultäten
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Ehemalige ProfessorInnen
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie mit Schwerpunkt Biophysikalische Chemie
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Ehemalige ProfessorInnen > Lehrstuhl Biopolymere - Univ.-Prof. Dr. Paul Rösch
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Ehemalige ProfessorInnen > Lehrstuhl Biopolymere - Apl. Prof. Dr. Birgitta Wöhrl
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie mit Schwerpunkt Biophysikalische Chemie > Lehrstuhl Biochemie mit Schwerpunkt Biophysikalische Chemie - Univ.-Prof. Dr. Janosch Hennig
Titel an der UBT entstanden: Ja
Themengebiete aus DDC: 500 Naturwissenschaften und Mathematik
500 Naturwissenschaften und Mathematik > 500 Naturwissenschaften
500 Naturwissenschaften und Mathematik > 540 Chemie
500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie
Eingestellt am: 15 Jan 2015 09:26
Letzte Änderung: 22 Dec 2023 12:24
URI: https://eref.uni-bayreuth.de/id/eprint/5566