- The microtubule protein tubulin is a heterodimer comprising α/β subunits, in which each subunit features multiple isotypes in vertebrates. For example, seven α-tubulin and eight β-tubulin isotypes in the human tubulin gene family vary mostly in the length and primary sequence of the disordered anionic carboxyl-terminal tails (CTTs). The biological reason for such sequence diversity remains a topic of vigorous enquiry. Here, we demonstrate that it may be a key feature of tubulin's role in regulation of the permeability of the mitochondrial outer membrane voltage-dependent anion channel (VDAC).
- Background: Tubulin C-terminal tail (CTT) peptides bind and block VDAC.Results: CTT-albumin chimeras show that a single CTT suffices for VDAC blockade and that CTTs differ in potency by more than an order of magnitude.Conclusion: Small sequence changes or post-translational modifications in CTT result in substantial changes in VDAC blockage.Significance: Disordered protein tails are not just charged strings, but embody nuanced interaction specificity.
- Background: Nearly all nascent mitochondrial proteins are transported by the translocase of the outer membrane (TOM) complex.Results: The core Tom40 β-barrel domain exhibits four conductive levels and three distinct substrate binding affinities.Conclusion: Tom40 interactions with presequence substrates depend upon the channel's conformation.Significance: Conformational rearrangements in Tom40 may regulate substrate interactions.
- Background The intrinsically disordered protein α-synuclein, a hallmark of Parkinson disease, is involved in mitochondrial dysfunction in neurodegeneration and directly interacts with mitochondria. Results α-Synuclein regulates VDAC permeability; α-synuclein toxicity in yeast depends on VDAC. Conclusion α-Synuclein both blocks VDAC and translocates via this channel across the mitochondrial outer membrane. Significance (Patho)physiological roles of monomeric α-synuclein may originate from its interaction with VDAC.