title: Structural insights into proapoptotic signaling mediated by MTCH2, VDAC2, TOM40 and TOM22.
abstract: Mitochondrial Outer Membrane (MOM) Permeabilization (MOMP) is a critical step in the intrinsic pathway of apoptosis and is regulated by the Bcl-2 family of proteins. In vitro studies using cardiolipin-containing liposomes as a MOM model have suggested that a mitochondria-specific phospholipid, cardiolipin, is of crucial importance in MOMP. However, recently it has been found that the MOM contains much less cardiolipin than it is required for liposome permeabilization. Shortly thereafter, several MOM proteins, such as VDAC2, MTCH2, TOM22 and TOM40, have been identified as the Bax, Bak and tBid receptors that are indispensable in MOMP, but the underlying mechanisms are elusive. Here, proapoptotic signaling mediated by these MOM receptors was explored in terms of 3D-structures of interacting proteins using computational modeling. The formation under apoptotic conditions of the TOM40/TOM22/tBid protein complex possessing a fairly high binding affinity towards Bax is predicted, suggesting the recruitment of Bax to mitochondria by this complex in apoptotic cells. Our simulations predict the displacement of Bax from the TOM40/TOM22/tBid/Bax complex by another Bax in auto-catalytic manner and explain, in terms of structure, the tBid-mediated displacement of Bak from the VDAC2/Bak complex. Computational modeling revealed high-affinity binding of Bid to MTCH2 suggesting both a quasi-constitutive residence of Bid in MTCH2-bound state in healthy cells and its caspase-8-mediated cleavage there under apoptotic conditions. Overall, our results provide structural details for important stages of apoptotic signaling mediated by MOM receptors and enrich its mechanistic understanding.
authors.affiliation: Department of Cell Biophysics, Institute of Biophysics and Cell Engineering of NAS of Belarus, Academicheskaya St. 27, Minsk 220072, Belarus. Electronic address: veresov@ibp.org.by.
authors.forename: Valery G
authors.initials: VG
authors.lastname: Veresov
authors.affiliation: Department of Cell Biophysics, Institute of Biophysics and Cell Engineering of NAS of Belarus, Academicheskaya St. 27, Minsk 220072, Belarus.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Davidovskii
mesh_terms: D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D030562:Databases, Protein; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D062105:Molecular Docking Simulation; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D050996:Voltage-Dependent Anion Channel 2 / Q000737:chemistry / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D050996:Voltage-Dependent Anion Channel 2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C502207:MTCH2 protein, human; C489971:TOMM22 protein, human; C494765:VDAC2 protein, human; C400783:TOMM40 protein, human
keywords: 3D-structure; Apoptotic signaling; MTCH2; TOM22; VDAC2