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Cell Proliferation and Underlying diseases > Protein phosphorylation and other post translational modifications > Flashcards

Protein phosphorylation and other post translational modifications Flashcards

1
Q

How is the dynamic-rapid response achieved?

A

Post translational modifications and not gene transcription regulation (takes too long)

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2
Q

What are post translational modifications?

A

Covalent modifications after translation

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3
Q

What is the eraser of ubiquitination?

A

Deubiquitinases (DUBs)

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4
Q

What are the 3 ubiquitin enzymes?

A

E1 - ubiquitin activating enzyme
E2 - ubiquitin conjugating enzyme
E3 - ubiquitin ligase

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5
Q

What are the 3 types of ubiquitination?

A
  • monoubiquitylation
  • multi-monoubiquitylation
  • polyubiquitylation
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6
Q

What are the four types of conformational change?

A

Local disruption
Local ordering
Long-range disruption
Long-range ordering

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7
Q

What are the effects of PTMs?

A

Conformational changes

Protein:protein interactions

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8
Q

Examples of protein:protein interactions

A

14-3-3 protein
bromodomains
SH2
PHD domains

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9
Q

What is the writer for acetylation?

A

Acetyltransferase

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10
Q

What is the eraser for acetylation?

A

deacetylase

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11
Q

What is the writer for methylation?

A

methyl-transferase

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12
Q

What is the eraser for methylation?

A

amine oxidase
demethylase
deiminase

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13
Q

What is the writer for proline hydoxylation?

A

prolyl hydroxylase

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14
Q

What are the roles of PTMs?

A 
Activity 
Localisation 
Stability 
DNA/ RNA binding 
Complex formation 
Selectivity
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15
Q

Example of PTM selectivity

A

PTM control selective activation of particular p53 target genes

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16
Q

Types of PTM crosswalk

A

Positive crosswalk

Negative crosswalk

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17
Q

What is positive crosswalk?

A

one PTM is a signal for the addition or removal of a second PTM

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18
Q

What is negative crosswalk?

A

Mutually exclusive - Direct competition for modifying a single residue
Antagonistic - indirectly by changing the recognition site for another PTM

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19
Q

How are PTMs measured?

A

Mass spec

Antibodies

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20
Q

What is mass spec?

A

An analytical tool which ionises chemical species and sorts the ions based on their mass-to-charge ratio.
Used to elucidate the chemical structures of molecules.

21
Q

How does mass spec work globally and on individual proteins?

A

Sample undergoes gas/ liquid chromatography
Undergo ionisation interface
Undergo mass spec

22
Q

How does mass spec work on only individual proteins?

A

Sample undergoes enzimatic digestion to form peptides
Undergoes gas/ liquid chromatography
Undergo ionisation interface
Undergo mass spec

23
Q

Advantages of mass spec

A
  • unbiased/ untargetted information
  • can differentiate very similar proteins/ isoforms
  • can generate a huge amount of information
  • quantitative
24
Q

Disadvantages of mass spec

A
  • expensive and time consuming
  • hard to pinpoint the position of the phosphorylation site
  • very abundant proteins will mask low abundance proteins
  • need expertise e.g. equipment
25
Q

What do antibodies recognise?

A

the modified group and part of the peptide surrounding it

26
Q

What modifications can antibodies recognise?

A

Methylation
Acetylation
Phosphorylation

27
Q

What modifications can antibodies not be used for?

A

Ubiquitylation

SUMOylation

28
Q

Advantages of using antibodies

A
  • cheap if they are available
  • specific
  • very sensitive
  • can identify subtle differences
  • give quantitative information
29
Q

Disadvantages of using antibodies

A
  • need to already know where it is modified and what type of modification
  • not antibodies available for each modified protein
  • producing new antibodies is expensive, time consuming and not always successful
30
Q

What is the basic structure of a protein kinase?

A

Conserved core
2 lobes
The active site (where the ATP binds) in the cleft between the two lobes

31
Q

What happens in the inactive form of a kinase?

A

C-helix out
R-spine disassembled
Activation loop disordered

32
Q

What happens in the active from of a kinase?

A

C-helix in
R-spine assembled
Activation loop ordered

33
Q

What determines kinase specificity?

A

The depth of the catalytic cleft
Peptide specificity
Distal docking sites
Targetting subunits

34
Q

How is peptide specificity determined?

A

depends on the kinase P+1 loop sequence

35
Q

What is distal docking sites mediated through?

A

binding domains outside the kinase active site and the substrate phosphorylation site

36
Q

explain targetting subunits

A

binding partners that contain docking domains that help to target the kinase to specific substrates

37
Q

What happens to tyrosine kinases in tumour cells?

A

Deregulated:

  • hyperactivating mutations
  • amplifications/ overexpression
  • loss of negative regulation
38
Q

what are the two types of protein kinase inhibitors?

A
  • Non-covalent inhibitors

- Covalent inhibitors

39
Q

What are the types of non-covalent inhibitors?

A

Type I - ATP-competitive = bind to the active conformation
Type II - non-ATP-competitive - bind to inactive conformation
Type III and IV - non-ATP- competitive - bind outside the ATP binding site (allosteric inhibition)

40
Q

Describe covalent inhibitors

A

Bind to the ATP-binding site
Not ATP competitive
Low selectivity

41
Q

Describe the use of chemical probes

A
  • ask a specific biological question
  • need biological validation
  • need specificity
  • need to have a define mechanism of action
  • bioavailability not needed
42
Q

Describe the use of drugs

A
  • need to be clinically safe and effective
  • need clinical validation
  • does not need to be specific
  • do not need a define mechanism of action
  • need human bioavailability and good pharmacokinetics
43
Q

What are the two types of resistance?

A

Primary resistance

Acquired resistance

44
Q

Explain primary resistance

A

de novo lack of treatment response

45
Q

What are the types of acquired resistance?

A
  • Target gene amplification
  • Target secondary mutations
  • Chromosomal alterations
  • Bypass of drug alteration
46
Q

Explain target gene amplification

A

Where the target is upregulated e.g. more kinase = drug less effective

47
Q

Explain target secondary mutations

A

mutations which result in reduced effectiveness to the drug

48
Q

Explain chromosomal alterations

A

Alternative splicing to hyperactive chimeric or truncated kinase

49
Q

Explain bypass of drug inhibition

A

Amplification of downstream signalling mediator

Cell Proliferation and Underlying diseases (12 decks)

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