Apoptosis regulator, Bcl-2 homologous antagonist/killer(BAK)
BAK is a family of Bcl-2 proteins that are central apoptosis regulators in mitochondia. There are two types of Bcl-2 family proteins which can be distinguished by their functions and characteristic amino acid motifs (Bcl-2 homology(BH) domains). Apoptosis activator proteins containing multiple BH domains (BH1-4) mediates mitochondrial outer-membrane permeabilization (MOMP) which induces the leakage of mitochondrial proteins such as cytochrome c and drives subsequent cell death. Apoptosis repressor proteins containing only BH3 domain, on the other hand, suppress the MOMP by apoptosis activator. BAK belongs to the former apoptosis activator proteins.
The structure of BAK lacking C terminal transmembrane domain(cBAK) is shown here. The C terminal domain of BAK is important for its function, because BAK with C terminal domain localizes on mitochondrial outermambrane, however, if the C terminal domain is cleaved by calcium dependent protease, calpain, BAK translocates to cytosol and MOMP is suppressed.
cBAK has the eight-helix globular structure observed in other BCL-2 family proteins (fig1). As shown fig2, α5-α6, α7-α8 and α3 form BH1, BH2 and BH3 domain respectively. In the other apoptosis activator proteins such as Bcl-x and BAX, three BH domains form a “pocket” where their regulators bind; the C terminal transmembrane domain binds to Bcl-x and a BH3 domain of apoptosis suppressor binds to BAX to suppress their function. Therefore, the pocket is considered important for the function of apoptosis activator proteins. However, in cBAK, the poket is too shallow to interact with its putative binding partner. Instead, zinc dependent dimerlization exists in BAK as a novel regulation mechanism. As shown in fig3, a zinc molecule is accommodated within the interface formed by the central helices of each subunit. Asp160 and His164 in α6 helix directly bind to the zinc. Although the precise mechanism which suppresses apoptosis by BAK dimerization is elusive, mutagenesis experiments suggested that His164 and Cys166 may be the critical residues to interact with unknown membrane apoptosis regulator.
fig1. The structure of cBAK. Eight helices(α1-8) are described. BH1,BH2 and BH3 domains are colored as aquqmqrine, skyblue and purple, respectively.
fig2. The surface structure of cBAK. Colors are the same as in fig1.
fig3. The structure of dimeric cBAK. A zinc ion is shown as a red sphere. The colors of each subunit are the same as in fig1.
Protein Data Bank (PDB)
Moldoveanu, T. Liu, Q. Tocilj, A. Watson, M. Shore, G. Gehring, K.; "The X-Ray Structure of a BAK Homodimer Reveals an Inhibitory Zinc Binding Site"; Mol.Cell; (2006) 24:677-688 PubMed:17157251.
author: Daisuke Ino