VDAC1

Key takeaways

VDAC1 belongs to biology; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect VDAC1 to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of VDAC1 from memory before moving on to harder problems.

Reference excerpt

Voltage-dependent anion-selective channel 1 (VDAC-1) is a beta barrel protein that in humans is encoded by the VDAC1 gene located on chromosome 5. It forms an ion channel in the outer mitochondrial membrane (OMM) and also the outer cell membrane. In the OMM, it allows ATP to diffuse out of the mitochondria into the cytoplasm. In the cell membrane, it is involved in volume regulation. Within all eukaryotic cells, mitochondria are responsible for synthesis of ATP among other metabolite needed for cell survival. VDAC1 therefore allows for communication between the mitochondrion and the cell mediating the balance between cell metabolism and cell death. Besides metabolic permeation, VDAC1 also acts as a scaffold for proteins such as hexokinase that can in turn regulate metabolism.

This protein is a voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms (VDAC2 and VDAC3), which are involved in the regulation of cell metabolism, mitochondrial apoptosis, and spermatogenesis. Over expression and misregulation of this pore could lead to apoptosis in the cell leading to a variety of diseases within the body. In particular, since VDAC1 is the major calcium ion transport channel, its dysfunction is implicated in cancer, Parkinson's (PD), and Alzheimer's disease. In addition, recent studies have shown that an over expression within the VDAC1 protein is linked to Type 2 Diabetes. Lund University released a study that demonstrated the effects of blocking VDAC1 over expression can prevent the spread of Type 2 Diabetes.

Structure

The three VDAC isoforms (VDAC1, VDAC2, and VDAC3) have highly conserved DNA sequences as well as 3D structures forming a wide β-barrel structure, inside of which the alpha helical N-terminal segment resides to partially close the pore. VDAC1's structure was solved by 3 independent labs by x-ray crystallography, Nuclear Magnetic Resonance (NMR) spectroscopy, or a combination of both. Two of these structural studies were used to determine human VDAC1 (hVDAC1) structure while X-ray crystallography was used to solve murine VDAC1 (mVDAC1) structure that differs from hVDAC1 by only two residues. These determined structures aligned with earlier circular dichroism studies that predicted the presence of alpha helix and β-strand domains. Structural analysis of mVDAC1's structure showed a barrel-like channel composed of 19 amphipathic β-strands, with the N-terminus and C-terminus both facing towards the inter membrane space of the mitochondrion. β-strands are connected via loops and are arranged in an anti-parallel pattern with the exception of β-strands 1 and 19 which are parallel. The pore has a height of 40 Ẳ, spans a distance of 27 Ẳ by 20 Ẳ at the openings and tapers down to 20 Ẳ by 14 Ẳ at the N-terminal α-helix segment in the open state. The closed state conformation has yet to be isolated and determined. Additionally, the N-terminus has an alpha helical segment that is held to the inside wall of the pore by hydrophobic interactions with residues on β-sheets 8-18. This N-terminus can serve as a scaffold for the movement of ions or attachment of proteins. One such example is seen as it is the docking site for HK1 binding. A significant residue to point out is the glutamate located at the 73rd residue on the amino acid chain (E73). This residue is found in VDAC1 and VDAC2 but not VDAC3. The side chain of this charged residue points into the phospholipid bilayer which would normally cause repulsive forces to occur. E73 however, has been implicated in VDAC1 function and interaction.

Function VDAC1 belongs to the mitochondrial porin family and is expected to share similar biological functions to the other VDAC isoforms. Of the three isoforms, VDAC1 is the main calcium ion transport channel in mitochondria and the most abundantly transcribed. VDAC1 is involved in cell metabolism by transporting ATP and other small metabolites across the outer mitochondrial membrane (OMM) allowing regulation of the TCA cycle and, by extension, reactive oxygen species (ROS) production. In yeast cells, ROS accumulate under conditions of oxidative stress, which results in impaired mitochondrial function and a "petite" phenotype. However, petite yeast cells exhibit a longer lifespan than wild-type cells and indicate a protective function by VDAC1 in similar circumstances, such as aging.

Voltage gating VDAC1 allows for the conductance of molecules into and out of the mitochondrion. Its permeability is dependent on VDAC1's conformational state which is determined by voltage. At low voltage (10mV), the pore is in an "open" state where the channel is weakly anion selective and allows for a greater flux of metabolites. Because of the large pore size, metabolic gating under saturated ATP conditions reveal a transport of 2,000,000 ATP/second and a transport of 10,000 ATP under physiological conditions. At a higher voltage in the positive or negative direction (>30mV), the pore is in a "closed" state and is weakly cation selective allowing for less metabolites to be transported. The flux of metabolites can be seen as negligible. This change in states is mediated by a conformational change in the protein that has yet to be discovered. Since the alpha helical N-terminus segment is located in the center of the pore, it is ideally situated for metabolic gating. This lead researchers to believe that the Alpha helix was a key contributor to determining the conformational states. However, more recent studies have shown the N-terminal is unnecessary for proper voltage gating and therefore suggest the flexible beta barrel as the mechanism of conformational change.

Oligomerization Atomic Force Microscopy (AFM) revealed the presence of VDAC1 monomers as well as dimers and larger oligomers showcasing the interaction of the pore with itself, however, dimers are more frequent. hVDAC1 in particular has been shown to arrange in parallel dimers leading to increased permeability of the pore. The glutamate located at the 73rd position on VDAC1 has also been shown to play a role in oligomerization when in the presence of calcium. VDACs can also oligomerize to form part of the mitochondrial permeability transition pore (MPTP) and, thus, facilitate cytochrome C release, leading to apoptosis. VDACs have also been observed to interact with pro- or antiapoptotic proteins, such as Bcl-2 family proteins and kinases, and so may contribute to apoptosis independently from the MPTP.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with VDAC1

Start with the simplest possible case. Write down what VDAC1 claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to VDAC1 before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about VDAC1 ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of VDAC1

In research: VDAC1 appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses VDAC1 in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: VDAC1 is common in secondary-school and first-year university syllabi. It links to neighbouring topics Human genes, Ion channels, so understanding it makes those chapters shorter.
In everyday life: Look for VDAC1 outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study VDAC1 in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what VDAC1 means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain VDAC1 out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is VDAC1 in simple terms?

Voltage-dependent anion-selective channel 1 (VDAC-1) is a beta barrel protein that in humans is encoded by the VDAC1 gene located on chromosome 5. It forms an ion channel in the outer mitochondrial membrane (OMM) and also the outer cell membrane.

Why does VDAC1 matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study VDAC1?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on VDAC1.