Microtubules

Question 1

Give general information on cytoskeleton

Answer 1

3 filaments = microtubules (MT), IFs, microfilaments (actin)
Dynamic: coordinated by themselves and ext signals
Function is support, str, intracell mvmt, cytokinesis, changes in cell shape
Motor protein: Myosin (Actin) Dynein and Kinesin (MTs)

Question 2

What is the function of MTs

Answer 2

Structural, rigid, organisation, railroad, intracell transport, spindle in mitosis, motile units

Question 3

What is the structure of MT

Answer 3

Straight hollow tubes 25nm Dia. Dimer = alpha and beta tubulin. Linear arrangement is 13 protofilaments. Alpha/Beta dimers polymerise end to end: alpha (- end) contacts beta (+ end) therefore it is polar

Question 4

Describe MT GTP cycle

Answer 4

beta tubulin capped with GTP and quickly hydrolyzed to GDP. GTP bound beta has high affinity for other subunits

Question 5

MT nucleation

Answer 5

beta tubulin GTP gradually hydrolyzed to GDP, if GDP reaches growing end = depolarisation and catastrophic. Increasing GTP-tubulin rescues

Question 6

Describe MT dynamic instability

Answer 6

Dimers = +/-‘d from hollow tube, dimers add more easily to pos end before GTP hydro. Growth rule = proportional to concentration of GTP-tubulin dimers. GTP region = growth up

Question 7

Describe configuration of MTs

Answer 7

Singles=13 proto = MT
Proto= 1x vert column of tublin dimers
Singlets= carry vesicles, organelles, chrom
Doublets= Cilia and Flagella = axoneme
Triplets = centrioles and basal bodies (MTOC)= 9 triplets

Question 8

MT directionality

Answer 8

• ends at MTOC near nuc, radiate out to periph
  Kinesin towards pos end, Dynein towards neg end
  With 2 ATPase heads

Question 9

What is the MTOC (MT orgo center)

Answer 9

Gamma tubulin = scaffold for growth
Centrosome = 2 centrioles perpendicular which organize and make pericentriole material (anchors and caps MT end)
MTs grow from gamma tubulin ring around centrioles
Basal bodies = MTOC under cilia and flagella

Question 10

What are the MT associated proteins (MAPs)

Answer 10

Protect from MT disassembly. Inhibits tubulin dissociation (tau). Links MTs together and to other structures

Question 11

What are the domains of MAPs

Answer 11

1. 2 tubulin binding domains (stab MTs)

2. 1 tubulin and 1 cell struc binding domain

Question 12

Describe the mitotic spindle

Answer 12

3 classes of MT: Astral (push apart) Kinetechore (and centromere and stabilize) Polar (push away).
Centrioles replicate prior to mitosis and go to spindle poles

Question 13

Rearrangement during mitosis

Answer 13

Chroms line at metaphase plane. MTs attach to kinetechores. Sister chromatids pulled apart. Dynein walks chrom along kine MTs to poles. MT short occurs. MT molecules on polar MT push them apart therefore elongating spindle and push poles apart.

Question 14

MT in Cilia and Flagella

Answer 14

Axoneme, Dynein, MTOC= basal body.
Axoneme = 9x2+2 arrangement. Basal body = 13 protofilaments. MT grow out of 2 of 3 MTs in 9 trips of BB (similar to centriole in struc)
Each outer MT doublet associated with In and Out Dynein arms which slide out MT doublets = wiggling motion.
Binding: Dynein motion, constrained by linkage proteins

Question 15

Describe Chediak Higashi Syndrom

Answer 15

Rare, AR, CHS1/LysT mutation. USMLE = defect in MT poly. Def of phage with lysosome leukocytes

Question 16

Describe primary Ciliary Dyskinesia (PCD)

Answer 16

Immotile cilia and sperm leading to retention of secretions and recurrent infection along with infertility.
50% = Kertagner Syndrome = Bronchiatis, Situs inversus, chronic paranasal sinusitis, infertlity.
Lack/defect of dynein arms/inner dynein arms = immobility

Question 17

Describe the drugs associated with MTs

Answer 17

1. Bind to tubulin subunits and prevent poly. Colchieine (gout) Vincristine and Vinblastine (treat cancer with increased motility index)
2. Bind and stabalize MTs (inhib depoly): Pacilitaxel (toxol) bloacks mitosis therefore treats cancer (can no longer break down mitotic spindle)

Question 18

What is Alzheimers

Answer 18

Hyperphos tau forms NFTS therefore decreasing functional MT depoly and axon transport. Autosomal dominant or multifactorial

Question 19

Describe Alzheimers disease path

Answer 19

Beta-amyloid/ senile plaques(extra cell) lead to progressive neuronal dmg. ApoE present. Beta amy plaques - neurofibril tangles - tau hyperphos forms NFTs and accumulate in beta amy plaques. MT depoly and disrupt of axon transport

Question 20

Describe early onset alzheimers

Answer 20

Autosomal dominant mutation. (less than 60 presents). Presinlin 1, presinilin 2, Beta-amyloid precursor (tri 21) are genes associated with early onset

Question 21

Describe alzheimer’s predispostion

Answer 21

Multifactorial, late onset (>60)
Apolipoprotein E (e4 allele): major genetic risk factor determining age of onset (earlier onset for both early and late onset)
ApoE2: reduced risk
1 allele ApoE4 = R x3
2 allele ApoE4 = Rx15 and earlier onset
50-75% E4 hetero never develop AD
35-50% AD have ApoE4 vs 15% gen pop