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Chapter 9
Intermediate Filaments
By
E. Birgitte Lane
9.1 Introduction
• Intermediate filaments are major
components of the nuclear and
cytoplasmic cytoskeletons.
• Intermediate filaments are essential to
maintain correct tissue structure and
function.
9.1
Introduction
• Intermediate filaments:
– are between actin filaments and
microtubules in diameter
– form robust networks
• Intermediate filaments are polymers of
protein subunits.
9.1
Introduction
• Intermediate filament proteins:
– are heterogeneous
– re encoded by a large and complex gene
superfamily
• Over 50 human diseases are
associated with intermediate filament
mutations.
9.2 The six intermediate filament protein
groups have similar structure but different
expression
• Intermediate filament proteins all share
a similar structure that is based on an
extended central α-helical rod domain.
• The intermediate filament family is
divided into six sequence homology
classes.
9.2 The six intermediate filament protein groups have similar structure but different
expression
• Different kinds of intermediate filaments
have different tissue expression
patterns.
• Antibodies to individual intermediate
filaments are important tools for
monitoring cell differentiation and
pathology.
9.3 The two largest intermediate filament
groups are type I and type II keratins
• Most of the intermediate filament
proteins in mammals are keratins.
• Keratins are obligate heteropolymers of
type I and type II proteins.
9.3 The two largest intermediate filament groups are type I and type II
keratins
• Paired keratin expression is predictive
of epithelial differentiation and
proliferative status.
• Simple keratins K8 and K18 are the
least specialized keratins.
9.3 The two largest intermediate filament groups are type I and type II
keratins
• Barrier keratins have the most complex
and varied expression of all
intermediate filaments.
• Structural keratins of hard appendages:
– are distinct from other keratins
– may be the latest–evolving mammalian
keratins
9.4 Mutations in keratins cause epithelial
cell fragility
• Mutations in K5 or K14 cause the skin
blistering disorder epidermolysis bullosa
simplex.
• Severe EBS mutations are associated
with accumulated nonfilamentous
keratin.
9.4 Mutations in keratins cause epithelial cell
fragility
• Many tissue fragility disorders with
diverse clinical phenotypes are caused
by structurally similar mutations in other
keratin genes.
• Cell fragility disorders provide clear
evidence of a tissue-reinforcing function
for keratin intermediate filaments.
9.5 Intermediate filaments of nerve,
muscle, and connective tissue often show
overlapping expression
• Some type III and type IV intermediate
filament proteins have overlapping
expression ranges.
• Many type III and type IV proteins can
coassemble with each other.
9.5 Intermediate filaments of nerve, muscle, and connective tissue often show overlapping
expression
• Coexpression of multiple types of
intermediate filament proteins may obscure
the effect of a mutation in one type of protein.
• Desmin is an essential muscle protein.
• Vimentin is often expressed in solitary cells.
• Mutations in type III or type IV genes are
usually associated with muscular or
neurological degenerative disorders.
9.6 Lamin intermediate filaments
reinforce the nuclear envelope
• Lamins are intranuclear, forming the
lamina that lines the nuclear envelope.
• Membrane anchorage sites are
generated by posttranslational
modifications of lamins.
9.6 Lamin intermediate filaments reinforce the nuclear
envelope
• Upon phosphorylation by Cdk1, lamin
filaments depolymerize.
– This allows disassembly of the nuclear
envelope during mitosis.
• Lamin genes undergo alternative
splicing.
9.7 Even the divergent lens filament
proteins are conserved in evolution
• The eye lens contains two highly
unusual intermediate filament proteins,
CP49 and filensin.
– These constitute the type VI sequence
homology group.
• These unusual intermediate filament
proteins are conserved in evolution of
vertebrates.
9.8 Intermediate filament subunits
assemble with high affinity into strainresistant structures
• In vitro, intermediate filament assembly
is rapid and requires no additional
factors.
• The central portion of all intermediate
filament proteins is a long α-helical rod
domain that forms dimers.
9.8 Intermediate filament subunits assemble with high affinity into strain-resistant
structures
• Assembly from antiparallel tetramers
determines the apolar nature of
cytoplasmic intermediate filaments.
• Intermediate filament networks:
– are stronger than actin filaments or
microtubules
– exhibit strain hardening under stress
9.9 Posttranslational modifications
regulate the configuration of intermediate
filament proteins
• Intermediate filaments:
– are dynamic
– show periodic rapid remodeling
• Several posttranslational modifications
affect the head and tail domains.
9.9 Posttranslational modifications regulate the configuration of intermediate filament
proteins
• Phosphorylation is the main mechanism
for intermediate filament remodeling in
cells.
• Proteolytic degradation:
– modulates protein quantity
– facilitates apoptosis
9.10 Proteins that associate with
intermediate filaments are facultative
rather than essential
• Intermediate filament proteins do not
need associated proteins for their
assembly.
• Specific intermediate filamentassociated proteins include:
– cell-cell and cell-matrix junction proteins
– terminal differentiation matrix proteins of
keratinocytes
9.10 Proteins that associate with intermediate filaments are facultative rather than
essential
• Transiently associated proteins include
the plakin family of diverse,
multifunctional cytoskeletal linkers.
9.11 Intermediate filament genes are
present throughout metazoan evolution
• Intermediate filament genes are present
in all metazoan genomes that have
been analyzed.
• The intermediate filament gene family
evolved by:
– duplication and translocation
– followed by further duplication events
9.11 Intermediate filament genes are present throughout metazoan
evolution
• Humans have 70 genes encoding
intermediate filament proteins.
• Human keratin genes are clustered.
– But nonkeratin intermediate filament genes
are dispersed.