Intermediate Filaments

What are intermediate filaments (IFs)?

Cytoskeletal filaments that are intermediate in size between actin filaments and microtubules.

What is the primary function of intermediate filaments?

To provide structural integrity and mechanical strength to cells and tissues.

Where are intermediate filaments mostly found?

In cells that require a lot of strength, e.g., epithelial cells of the skin and cardiac muscle.

Do cells express multiple types of intermediate filaments?

Typically, each cell expresses one type of cytoplasmic IF and a separate nuclear IF.

What forces do intermediate filaments resist?

Compression, twisting, stretching, and bending forces.

How do intermediate filaments respond to mechanical stress compared to actin and microtubules?

IFs are easily deformed but resist rupture; actin is rigid but can rupture, and microtubules are easily deformed and rupture easily.

What role do desmosomes play in IF function?

Desmosomes adhere adjacent cells together, helping IFs provide mechanical strength in tissues under intense stress.

How do intermediate filaments function as scaffolds?

They link cells together and organize cell contents, including organelles, actin filaments, and microtubules.

What property makes intermediate filaments particularly well-suited to maintain cell integrity?

Their ability to deform under stress without rupturing.

How diverse are intermediate filaments in humans?

Humans encode ~70 different intermediate filament genes.

Do most cells express multiple types of IFs?

Most cells express one type of cytoplasmic IF plus a nuclear IF (lamins), depending on the cell type.

How are IFs used in forensic or oncology applications?

They help determine the origin of a metastasized tumor by identifying the IF type expressed.

What is the structure of IF proteins?

They have variable N- and C-terminal domains and a well-conserved central rod domain.

What is the role of the rod domain in IF proteins?

It forms α-helices that dimerize into a coiled-coil; important for dimerization and filament assembly.

Are intermediate filaments polar or non-polar?

IFs assemble into non-polar filaments; anti-parallel tetramers cancel the polarity of the coiled-coil dimers.

Do IFs require nucleotide binding or hydrolysis for assembly?

No, unlike actin or microtubules, IF assembly does not require ATP or GTP.

How stable are intermediate filaments?

They form super stable polymers resistant to mechanical stress and can survive even cell death.

Can IFs be dynamic?

Yes. Examples include keratin remodeling in hair (perms) and disassembly during mitosis.

How are IFs disassembled during mitosis?

They are phosphorylated to promote disassembly, allowing spindle formation for chromosome segregation.

How does keratin-based IF dynamics work in hair?

Disulfide bonds are broken (e.g., ammonium thioglycolate during a perm), hair is reshaped, and then disulfides are reformed (H2O2).

What is the main function of lamins?

Lamins form a meshwork structure that supports the nucleus, providing mechanical integrity and determining nuclear size and shape.

Where are lamins located in the cell?

They are on the inner face of the nuclear envelope in nucleated human cells.

What is the smallest functional unit of lamins?

Dimers, which oligomerize to form the nuclear lamina meshwork.

How are lamins targeted to the nucleus?

They have an NLS (nuclear localization signal) sequence that targets them to the nucleus.

How are lamins associated with the nuclear membrane?

Through a CAAX box modification (farnesylation), which inserts the protein into the nuclear envelope.

Are lamins permanently anchored to the nuclear membrane?

No, they are held in position mainly by interactions with other proteins but are not locked to the membrane.

What role do lamins play in nuclear migration?

Lamins maintain nuclear stiffness and prevent deformation during movement, as shown in micropipette aspiration experiments.

What diseases are associated with lamin mutations?

Over 180 mutations in Lamin A and B are linked to about a dozen diseases, including Hutchinson-Gilford Progeria (HGP).

How does Hutchinson-Gilford Progeria (HGP) relate to lamins?

A truncated Lamin A prevents farnesyl group cleavage, perturbing the lamin meshwork and causing disease.

What are keratins?

Keratins are cytoplasmic intermediate filaments expressed in epithelial cells, with over 50 types, and are very diverse.

Where are keratins expressed?

Different keratins are expressed at different levels of the skin.

What is the main function of keratins?

They provide mechanical strength and establish connections between cells via desmosomes and to the basal lamina via hemidesmosomes.

What happens if keratins are mutated?

Mutations lead to skin disorders such as Epidermolysis Bullosa Simplex, where skin blisters with minimal mechanical stress.

What are neurofilaments?

Neurofilaments are intermediate filaments found in neurons, especially in long axons.

What is the role of neurofilaments in axons?

They provide strength and stability, influence axon diameter, and affect the speed of electrical impulse propagation.

How do neurofilaments affect axon diameter?

More neurofilaments result in a larger axon diameter, which increases conduction speed.

Why are neurofilaments important for human health?

Abnormal neurofilament assembly and accumulation are linked to neurodegenerative diseases such as ALS, leading to impaired axonal transport, axon degeneration, and muscle weakness/atrophy.

What is desmin?

Desmin is an intermediate filament found in muscle cells.

What is the main role of desmin?

It helps organize muscle cell architecture, particularly around myofibrils.

How does desmin interact with myofibrils?

Desmin forms a "basket" around the myofibrils, supporting the contractile apparatus.

What additional function might desmin have?

It may help resist excessive stretching of muscle, though this is not fully clear.

What are IF-associated proteins?

Proteins that interact with intermediate filaments to crosslink them or anchor them to other structures.

What is the function of plectins?

Plectins are the largest family of IF-associated proteins; they can crosslink intermediate filaments to each other, and to microtubules or actin.