Intermediate filaments, Its
structures,Functions and Diseases
associated with it
Intermediate Filaments
Intermediate filaments are the medium-sized protein filaments that make up the
cytoskeleton. They are important for structure and support and tend to form
more permanent structures compared to microtubules or microfilaments. As a
result, they are an integral part of the cytoskeletal system and bear most of the
tension inside the cell. Intermediate filaments are a primary component of the
cytoskeleton, although they are not found in all eukaryotes, and are absent in
fungi and plants. These filaments, which extend throughout the cytoplasm and
inner nuclear membrane are composed from a large family of proteins that can
be broadly grouped into five classes.IF assembly begins with the folding of IF
proteins into a conserved alpha-helical rod shape, followed by a series of
polymerization and annealing events that lead to the formation of filaments
roughly 8 to 12 nm in diameter. Different IF combinations are found in different
cell types, however not all IF classes will interact with each other. In contrast to
other cytoskeletal components (e.g. actin filaments, microtubules), intermediate
filaments lack polarity, are more stable and their constituent subunits do not bind
nucleotides (such as ATP).
Structure of Intermediate filament
• Intermediate filaments are a diverse group of proteins. They can be
made of many different proteins,
including:Keratin,Desmin,Lamin,Vimentin,Neurofilaments.There are
over fifty different proteins that make up intermediate filaments.
However, despite their diverse structure and function, all intermediate
filaments have some features in common. Intermediate filaments
consist of a central alpha-helical rod domain. The domain is composed
of four alpha-helical segments, 1A, 1B, 2A, and 2B. Each segment is
separated by three linker regions. The central building block of an
intermediate filament is a pair of two intertwined proteins, called a
coiled-coil structure. The average diameter of intermediate filaments is
10 nm.Intermediate filaments are shaped like a helix, with two strands
of proteins twisted together. The individual subunits of the proteins
form dimers, and those dimers come together to form tetramers. The
tetramers assemble end to end overlapping as protofilaments.
Functions of Intermediate Filaments
• The tight association between protofilaments provide intermediate
filaments with a high tensile strength. This makes them the most stable
component of the cytoskeleton. Intermediate filaments are therefore
found in particularly durable structures such as hair, scales and
fingernails.The primary function of intermediate filaments is to create cell
cohesion and prevent the acute fracture of epithelial cell sheets under
tension. This is made possible by extensive interactions between the
constituent protofilaments of an intermediate filament, which enhance its
resistance to compression, twisting, stretching and bending forces. These
properties also allow intermediate filaments to help stabilize the extended
axons of nerve cells, as well as line the inner face of the nuclear envelope
where they help harness and protect the cell’s DNA.
Functions of Intermediate cells
• Intermediate filaments provide structural support, regulate
key signaling pathways, and facilitate the movement of
proteins to specific domains of polarized cells, such as Sertoli
cells. The main function of intermediate filaments is to
provide support and structure for cells. The intermediate
filaments are a permanent part of the cytoskeleton and help
provide structure for the cell. They are also essential in
anchoring the cell to other cells, called cell cohesion, and to
the extracellular matrix. Intermediate filaments have great
tensile strength, and their main function is to enable cells to
withstand the mechanical stress that occurs when cells are
stretched.
Intermediate Filament protein classes,
structure and functions
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Type I and II: KeratinsType
III: Desmin, vimentinType
IV: NeurofilamentsType
V: Lamins
Keratin proteins comprise the two largest classes of intermediate filament proteins. Historically,
the two types of keratin were grouped as acidic (type I) or basic (type II) according to the overall
physical properties of their composite amino acids. Keratin proteins first assemble into dimers,
with one acidic and one basic chain, then into protofilaments and finally into IFs. In 2006, a
universal nomenclature for each of the then known keratin genes and proteins, which totaled 54
(28 type I and 26 type II), was established to achieve international consensus for their naming and
classification [3].The expression of particular acidic and basic keratins can be cell type specific.
Keratins are found in epithelial tissues and their expression can be altered during the lifetime of a
cell. Keratins provide vital internal support and cohesion to epithelial cell sheets. For example,
t).he basal layer of epithelial cells that constantly divide and give rise to new skin cells
(keratinocytes) become filled with keratin filaments as they mature. The keratin filaments anchor
the skin cells to the extracellular matrix (ECM) at their base and to adjacent cells at their sides,
through structures called hemidesmosomes and desmosomes, respectively. As these skin cells
die, the layer of dead cells form an essential barrier to water loss. Consequently, mutations in
keratin genes are known to be responsible for a variety of skin diseases. Keratin-containing
structures are also located external to the epithelial cell layer (e.g. hair and nails).
Vimentin and desmin
• Vimentin is a type III intermediate filament protein, primarily
expressed in mesenchymal cells and plays a vital role in regulating cell
shape and in maintaining cytoplasmic integrity. Vimentin also
functions as an organizer of key signaling and adhesion proteins
involved in processes like cell adhesion, migration and signaling.
• Desmin is a type III intermediate filament protein expressed in
striated, smooth and cardiac muscle cells and aids in maintaining the
structural and mechanical integrity of the contractile apparatus of the
muscle tissue, by forming fibrous networks that interconnect
Lamin
• The lamin family of proteins are the constituent proteins of the
nuclear lamina, a fibrous protein matrix located on the nucleoplasmic
side of the inner nuclear membrane, and play a role in maintaining
nuclear stability, chromatin organization and modulating gene
expression. Mammalian lamins are primarily of two types- Lamin A/C
and Lamin B.
Diseases/Disorders associated with
Intermediate Filament
• A common feature of many intermediate filament–related disorders,
including skin disorders, liver disease, desmin myopathy, and
Alexander disease, is the occurrence of cytoplasmic inclusion bodies.
• (a) Alexander Disease
• (b) Charcot-Marie-Tooth Disease
• (c) Werner’s syndrome
• (d) Alzheimer's disease
• (e) Parkinson's disease
Alexander Disease
• Alexander disease is caused by dominantly acting mutations in glial
fibrillary acidic protein (GFAP), the major intermediate filament of
astrocytes in the central nervous system.
• Alexander disease is a rare disorder of the nervous system. It is one of
a group of disorders, called leukodystrophies, that involve the
destruction of myelin. Myelin is the fatty covering that insulates nerve
fibers and promotes the rapid transmission of nerve impulses.
Charcot-Marie Tooth Disease
• A group of hereditary disorders that damage the nerves in the arms and
legs.Charcot-Marie-Tooth is a degenerative nerve disease that usually
appears in adolescence or early adulthood. Charcot-Marie-Tooth disease is
an inherited, genetic condition. It occurs when there are mutations in the
genes that affect the nerves in your feet, legs, hands and arms. Sometimes,
these mutations damage the nerves. Other mutations damage the
protective coating that surrounds the nerve (myelin sheath).
• Charcot–Marie–Tooth disease (CMT) is the most common inherited
disorder of the peripheral nervous system, and mutations in
neurofilaments have been linked to some forms of CMT. Neurofilaments
are the major intermediate filaments of neurones, but the mechanisms by
which the CMT mutations induce disease are not known.
Werner’s Syndrome
• Werner syndrome, also called progeria, is a hereditary condition
associated with premature aging and an increased risk of cancer and
other diseases. Signs of Werner syndrome usually develop in the
childhood or teenage years.
• Werner syndrome is caused by mutations in the WRN gene and is
inherited in an autosomal recessive manner. This condition is
diagnosed based on the symptoms and genetic testing . Treatment is
based on individual symptoms and focuses on prevention of heart
disease and cancer.
Alzheimer's disease
• Alzheimer's disease is a progressive neurologic disorder that causes
the brain to shrink (atrophy) and brain cells to die. Alzheimer's
disease is the most common cause of dementia — a continuous
decline in thinking, behavioral and social skills that affects a person's
ability to function independently.
• Alzheimer's disease is thought to be caused by the abnormal build-up
of proteins in and around brain cells. One of the proteins involved is
called amyloid, deposits of which form plaques around brain cells.
The other protein is called tau, deposits of which form tangles within
brain cells.
Parkinson's disease
• Parkinson's disease is a progressive nervous system disorder that affects
movement. A disorder of the central nervous system that affects movement,
often including tremors.
• In Parkinson's disease, certain nerve cells (neurons) in the brain gradually break
down or die. Many of the symptoms are due to a loss of neurons that produce a
chemical messenger in your brain called dopamine. When dopamine levels
decrease, it causes abnormal brain activity, leading to impaired movement and
other symptoms of Parkinson's disease.The cause of Parkinson's disease is
unknown, but several factors appear to play a role, including:Genes. Researchers
have identified specific genetic mutations that can cause Parkinson's disease. But
these are uncommon except in rare cases with many family members affected by
Parkinson's disease.However, certain gene variations appear to increase the risk
of Parkinson's disease but with a relatively small risk of Parkinson's disease for
each of these genetic markers.Environmental triggers. Exposure to certain toxins
or environmental factors may increase the risk of later Parkinson's disease, but
the risk is relatively small.
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