Lecture 15 -Membrane trafficking in disease Flashcards

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1
Q

What are rab proteins and their role in cellular trafficking?

A

Rab proteins are a member of the Rat superfamily.
They cycle between GDP + GTP form

GDP = cytoplasm, GTP = membrane

They are required for fusion and many other trafficking functions.

It is found in the early stages of endosyti pathway.

Allows sophisticated regulation of trafficking steps

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2
Q

What does the Golgi do ?

A

It sorts out everything during vesicle transport. It distributes proteins and lipids from the ER and packages them in vesicles and passes them to the plasma membrane.

After protein is synthesised the Golgi modifies and adds oligosaccharides on the asparagine residues.

The protein will be sent to the lysosome. Endosomes will take matreil form out of cell or Golgi and will send them to either, lysosome, membrane or Golgi for more use.

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3
Q

What does SRP stand for ?

A

Signal recognition particle.

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4
Q

What does the SRP do ?

A

Will transport the protein-ribosome complex to the rough ER by docking onto SRP receptor. Allows protein translated and transported

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5
Q

What happens if SRP is defective or absent ?

A

The excess protein accumulates in cytosol

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6
Q

What are the 3 types of vesicular trafficking coat proteins?

A

COPI protein that coats the vesicle for retrograde transport. Will bring the vesicle from the cisgolgi to ER), retro because its moving towards centre of cell.

COPII. Coats vesicles for anterograde transport. Will bring the vesicle from the ER to the cis-golgi

Clathrin transports protein from trans-Golgi to lysosomes or plasma membrane to lysosome through receptor-mediated endocytosis

They form coats around membranes to force the creation of a protein. They work by binding a portion of the membrane and bud iff piece of membrane to make a vesicle

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7
Q

What are the 2 main types of protein trafficking?

A

Vesicle-mediated trafficking and non-vesicle mediated

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8
Q

Describe ER targeting

A

Mature mRNA leaves nucleus ro dinf a free floating ribosome.

Transation and protein starts forming, SRP recignises a unique a in growing polypeptide chain.

SRP brid to this aa sequence.

It binds a pore in ER membrane and brings ribsome-protein complex into ER.

The rest of the protein is synthesised in ER an protein becomes part of ER vesicular transport system.

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9
Q

What is endocytosis ?

A

Cells use this process to take in foreign material into the cell by making vesicle from the plasma membranes.

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10
Q

What are the 2 sides of golgi ?

A

Side that faces ER and the one that faces plasma membrane

Sis- golgi - ER immature proteins
Trans-golgi - membrane - mature proteins that are ready to be sent out

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11
Q

What is the difference between contistuitvie secretion and regulated ?

A

Constitutive - vesicles are constantly, undergoing exocytosis. - default pathway
Regulated - loaded vesicles are stored in cytosol until a release signal is recieved.

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12
Q

What does a mutations in the SEC23A gene disrupt ?

A

Mutations in the SEC23A gene disrupt the normal function of the protein it encodes, which is a component of the COPII protein complex. The COPII complex is responsible for packaging proteins into transport vesicles that bud off from the endoplasmic reticulum (ER) and deliver the proteins to the Golgi apparatus for further processing and sorting.

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13
Q

What does disrupted protein trafficking lead to other than CLSD ?

A

Disrupted protein trafficking can subsequently affect the activity and function of Rab proteins, as they are involved in various steps of vesicular transport.

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14
Q

What do Adaptor proteins do?

A

Recognise and select cargo ensuring specificity.
They link the coat to the membrane- > coat protein has no lipid binding proteins

Adaptors recognise motifs in the cytoplasmic domains of membrane proteins -> go to correct membrane

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15
Q

How do adaptor complexes show a precise sub cellular localisation ?

A

Need to link to the correct membrane
Proteins are specific for cargo and location.
AP1 - localised on Endosome and TGN
AP2 - Plasma membrane
AP3 - TGN, lysosomal related organelles

These proteins have similar structures and recognise similar structures and recognise similar signals

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16
Q

What sort of peptide motifs does AP2 recognise?

A

gamma and 6 subunits recognise sorting signals
Appendages interact with many proteins
B2 binds Cathrin
AP2 is a major Cathrin adaptor

17
Q

Why are only some tissues affected ?

A

different levels of expression and different copies of proteins = Functional redundancy

18
Q

What is Cranio- lenticuio-sutural dysplasia ?

A

A rare autosomal recessive disease.
The hypo mobility causes musculoskeletal issues.
The Fontinella is o0pen

There’s a problem in deposition of ECM in bone and muscle (collagen).

Due to point mutation. Phenylalanine to Leucine

19
Q

What are the differences between the WT and Mutant mice in an experiment about Cranio- lenticuio-sutural dysplasia?

A

WT - many exit sites form, protein coats form and are recruited to ER membrane

Mutant - ER VERY distended, problem with packaging COPII vesicles at ER

20
Q

What is COPII formation and ER membrane presence measure by ?

A

COPII - levels of cargo (p58)

ER membrane - levels of Ribophorin

21
Q

Are liposomes affected by binding of mutant Sec23A?

A

Binding of mutant to liposomes is unaffected.
Both WT and mutant Sec23 able to bind well to GTP form of SAR1

22
Q

What do you need to incubate with ER membranes in order to produce COPII?

A

Add cytosol = no COPII
Add cytosol, ATP, GTP = COPII formed
Mutant Sec23A = less COPII formed

23
Q

How is the packaging of large cargo done?

A

Done by modification of COPII coat
A defect in COPII causes defect in large cargo movement such as collagen.

24
Q

How does Rob fusion occur?

A

Rabs pull in vesicles in order to interact with a tethering protein

This allows SNARE complexes to form.

Tethering protein associates with organelles and other part free in cytoplasm.

Rob interacts with this part of tether and a Rab on the membrane interacts with anchored part

25
Q

What do Rab cascades allow?

A

Allow movement of cargo between organelles

26
Q

What can GAPS do for Rabs ?

A

GAPS can recruit GEFs for the next Rab positive compartment .e.g. GAP for Rab5 can recruit GEF for Rab7