Intermediate Filaments

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Chapter 9

• Intermediate Filaments
• By
• E. Birgitte Lane

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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.

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9.1 Introduction

• Intermediate filaments
• are between actin filaments and microtubules in
  diameter
• form robust networks
• Intermediate filaments are polymers of protein
  subunits.

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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.

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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 a-helical rod domain.
• The intermediate filament family is divided into
  six sequence homology classes.

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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.

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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.

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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.

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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 latestevolving mammalian keratins

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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9.8 Intermediate filament subunits assemble with
high affinity into strain-resistant structures

• In vitro, intermediate filament assembly is rapid
  and requires no additional factors.
• The central portion of all intermediate filament
  proteins is a long a-helical rod domain that
  forms dimers.

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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

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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.

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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

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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 filament-associated
  proteins include
• cell-cell and cell-matrix junction proteins
• terminal differentiation matrix proteins of
  keratinocytes

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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.

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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

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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.