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4 Types of Intermediate Filaments

1. Keratins
2. Vimentin-family
3. Neurofilament proteins
4. Nuclear lamins

1

Properties of Intermediate Filaments

- No structural polarity
- Not useful as motility tracks
- High tensile strength

2

Structure of Intermediate Filaments

- Monomers: rod-like proteins with small globular ends
- Associate into homo- or hetero-dimers via tetrameric intermediates (don't require cofactors, relatively stable)
- Dimers --> large bundles w/out structural polarity

3

Keratins

- Cytoplasmic
- Epithelial cells, hair, nails, etc.
- Diverse family of proteins, co-assemble to form mixed filaments
- Main function = provide strength
- Essential for the body surface barrier function of skin

4

Vimentin Family

- Cytoplasmic
- Vimentin: in cells of mesodermal origin
- Desmin: in muscle cells - holds together adj. myofibrils
- GFA (Glial Fibrillary Acidic Protein): in astrocytes and glial cells (CNS support cells)

5

Neurofilaments

- Cytoplasmic
- In neurons: 3 subunits co-assemble into filaments that extend along axon
- Provide axon extensions with tensile strength

6

Nuclear Lamins

- nuclear
- meshwork on inner surface of nuclear membrane of all cells
- most dynamic IF (disassemble/reassemble during mitosis - regulated by phosphorylation/dephosphorylation)

7

Medical issues related to IF

- Progeria (premature aging): caused by Lamin A mutation
- Cancer diagnosis/treatment: type of IF proteins made can reveal tissue type of origin. Keratin typing esp. useful in identifying epithelial cancers
- Keratin mutations cause skin blister disease

8

Microtubule Properties

- dynamic
- structural polarity
- motility tracks
- Dyneins and kinesins: motors that move organelles/chromosomes along microtubules

9

Microtubule structure

- Hollow tube with a wall of 13 rows of subunits (alpha/beta dimers, contain GTP binding sites)
- Overall polarity: dimers all assemble in the same orientation along each row of MT
- Assembly requires Mg2+ and GTP

10

Microtubule Assembly

- DYNAMIC INSTABILITY
- Requires GTP, Mg2+, and a critical subunit concentration
- Assembly/disassembly both on + side
- Tubulin binds GTP
- Beta tubulin assembled in dimers can hydrolyze its GTP-> GDP
- Assembly faster than hydrolysis = growth
- Assembly slower than hydrolysis = unstable, shrink rapidly
- Unstable MT rescued by binding new GTP dimers at end, resume growth

11

Anti-microtubule drugs

1. Colchicine: blocks MT assembly by binding free tubulin, therapeutic for gout. Also anti-mitotic: disrupt mitotic spindle of dividing cells
2. Anti-cancer (chemotherapy) agents:
- Vinblastine/vincristine (block MT assembly, anti-mitotic, kills dividing cells);
- Taxol: binds/stabilizes MTs and arrests dividing cells in mitosis

12

Microtubule Organizing Centers (MTOCs)

- centrosome = paired centrioles and surrounding material
- negative end attached to MTOC
- nucleating sites where + ends easily add, made of gamma tubulin

13

Microtubule Maturation

- no longer show dynamic instability
- post-translational modifications: acetylation and detryosination of alpha tubulin contributes to stability
- ex. in cilia and nerve axons

14

Microtubule-associated proteins

- may be stabilized by capping proteins or microtubule-associated proteins (MAPs) - decrease probability of disassembly
- proteins change surface of the microtubule for interaction with other cellular proteins
- ex. MAP2 and tau in nerve cells

15

Dynein

- microtubule motor, carries heavy cargo (i.e. nucleus. Golgi, vesicles, MTs in mitotic spindle)
- Uses ATP hydrolysis to do mechanical work
- Move toward - end
- "inward" transport (e.g. recycled membrane)
- one and three headed - cilia and flagella
- keeps Golgi near the nucleus

- two headed - cytoplasmic dyenins

16

Kinesins

Microtubule motor, carries cargo (ER network. mitotic/meiotic spindles, small vesicles (synaptic vesicles))
+ end directed motility
Uses ATP hydrolysis
Two headed ATPases
Outward transport (e.g. neurotransmitters)
Stretches the ER from nuclear out toward MT + ends

17

Primary Ciliary Dyskinesia (PCD) aka Kartagener's Syndrome

- Mutations affecting ciliary motility - defective motile cilia
- Causes infertility (males), respiratory infections, developmental asymmetry defects

18

Polycystic Kidney Disease (PKD)

- mutations affecting ciliary membrane receptors
- caused by lack of receptors in membrane of non-motile cilia (needed for sensory systems and during limb development)
- loss of these cilia = wide range of symptoms