title: Structural transition in Bcl-xL and its potential association with mitochondrial calcium ion transport.
abstract: Bcl-2 family proteins are key regulators for cellular homeostasis in response to apoptotic stimuli. Bcl-xL, an antiapoptotic Bcl-2 family member, undergoes conformational transitions, which leads to two conformational states: the cytoplasmic and membrane-bound. Here we present the crystal and small-angle X-ray scattering (SAXS) structures of Bcl-xL treated with the mild detergent n-Octyl β-D-Maltoside (OM). The detergent-treated Bcl-xL forms a dimer through three-dimensional domain swapping (3DDS) by swapping helices α6-α8 between two monomers. Unlike Bax, a proapoptotic member of the Bcl-2 family, Bcl-xL is not converted to 3DDS homodimer upon binding BH3 peptides and ABT-737, a BH3 mimetic drug. We also designed Bcl-xL mutants which cannot dimerize and show that these mutants reduced mitochondrial calcium uptake in MEF cells. This illustrates the structural plasticity in Bcl-xL providing hints toward the probable molecular mechanism for Bcl-xL to play a regulatory role in mitochondrial calcium ion transport.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Rajan
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Minjoo
authors.initials: M
authors.lastname: Choi
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Quoc Toan
authors.initials: QT
authors.lastname: Nguyen
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Hui Ting
authors.initials: HT
authors.lastname: Toh
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), Singapore 138669.
authors.forename: CongBao
authors.initials: C
authors.lastname: Kang
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Singapore 138671.
authors.forename: Neelagandan
authors.initials: N
authors.lastname: Kamariah
authors.affiliation: Molecular Targets Program, James Graham Brown Center and Department of Medicine, Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
authors.forename: Huiya
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: White
authors.affiliation: Department of Genetic Engineering, College of Life Sciences, Kyung Hee University, Yongin-si, Gyeonggi-do, 446-701, Republic of Korea.
authors.forename: Kwanghee
authors.initials: K
authors.lastname: Baek
authors.affiliation: 1] School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551 [2] Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Singapore 138671.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Grüber
authors.affiliation: 1] School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551 [2] Department of Genetic Engineering, College of Life Sciences, Kyung Hee University, Yongin-si, Gyeonggi-do, 446-701, Republic of Korea.
authors.forename: Ho Sup
authors.initials: HS
authors.lastname: Yoon
mesh_terms: D000818:Animals; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D017136:Ion Transport; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000494:pharmacology; D053838:Scattering, Small Angle; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C474007:Bax protein (53-86); D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D002118:Calcium