Molecular Biophysics
Sequence diversity of tubulin isotypes in regulation of the mitochondrial voltage-dependent anion channel
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).Tubulin Tail Sequences and Post-translational Modifications Regulate Closure of Mitochondrial 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.Evidence of Distinct Channel Conformations and Substrate Binding Affinities for the Mitochondrial Outer Membrane Protein Translocase Pore Tom40
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.α-Synuclein Shows High Affinity Interaction with Voltage-dependent Anion Channel, Suggesting Mechanisms of Mitochondrial Regulation and Toxicity in Parkinson Disease
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.
