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Ubiquitin Signalling (1) Flashcards

1
Q

What happens if mutated proteins are degraded?

A

Get accumulation of the mutated proteins leading to toxic protein aggregates

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2
Q

What are the two main cellular pathway which result in the disposal of damaged or misfolded proteins?

A

Autophagy pathway

Proteasomal pathway

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3
Q

Out of 22k genes which are encoded in human cells, how many are part of the ubiquitin system?

A

~1,000

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4
Q

How many amino acids are in a ubiquitin molecule?

A

76

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5
Q

How does ubiquitin bind to proteins?

A

Post translationally via lysine residues

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6
Q

What are isopeptides?

A

A bond between the C-terminus of ubiquitin and the epsilon minor groups of the side chain of the lysine residue

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7
Q

What do isopeptide bonds provide?

A

Flexibility

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8
Q

How does the addition of ubiquitin alter the proteins function?

A

Target it for degradation
Changes its subcellular location
Bind to downstream effector

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9
Q

How many different lysine residues can ubiquitin bind to?

A

7 different lysine residues

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10
Q

As well as lysine, what other site can ubiquitin bind to? And what type of bond does it form?

A

N-terminal Methionine

Peptide bond

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11
Q

What is monoubiquitylation?

A

Addition of a single ubiquitin onto a substrate

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12
Q

What is multiple ubiquitylation?

A

Multiple lysine residues on a single substrate are modified with Ub

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13
Q

What is polyubiquitylation?

A

Addition of Ub onto more Ub

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14
Q

What is heterotypic polyubiquitylation?

A

Polyubiquitin chains with different linkages

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15
Q

What are the two types of heterotypic polyubiquitylation?

A

Mixed

Branched

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16
Q

What is mixed heterotypic polyubiquitylation?

A

Can start off with Ubs being via one link and then changes to a different linkage e.g. K63 to begin with and then K48

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17
Q

What is branched heterotypic polyubiquitylation?

A

You have a polyubiquitylated chain, then one of the Ub have 2 linkages and forms a branch

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18
Q

What post translational modifications can happen to Ub?

A

Phosphorylated
Acetylated
Addition of other ubiquitin like modifiers

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19
Q

Name 2 examples of Ub like modifiers

A

SUMO

NedA

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20
Q

How does ubiqutylation regulate downstream cellular processes?

A

Proteins with ubiquitin binding domains (UBDs) will recognises the Ub signals and couple to downstream responses

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21
Q

How is Ub controlled and regulated?

A

By deubiquitinases (DUBs)

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22
Q

What do DUBs do to Ub?

A

They cleave isopeptide bond between the Ub and its substrate or between Ub molecules -> reverse the protein signal e.g. stop it being degraded by the proteasome
Antagonise the function of E3

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23
Q

How many DUBs are there?

A

~100

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24
Q

How many UBDs are there?

A

~20

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25
Q

How many proteins contain UBDs?

A

~250

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26
Q

How many E1 are there?

A

~2

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27
Q

How many E2 are there?

28
Q

How many E3 are there?

29
Q

How many proteins are regulated by Ub?

30
Q

What is Lys48 involved in?

A

Proteasomal degradation

31
Q

What is Lys63 involved in?

A

NF-kappaB signalling (PAK1 is activated by Lys63 polyUb -> NF-kappaB)

32
Q

What is Met1 involved in?

A

TNFR signalling (by activating IKK)

33
Q

What is Lys6 involved in?

A

DNA damage response and dispose of damaged mitochondria by autophagy

34
Q

What are the 4 Ub patches?

A

Ile44 patch
Phe4 patch
Ile36 patch
Asp58

35
Q

What is the function of the patches?

A

To recognise different chains

36
Q

Give the structure of Lys6-linked diubiquitin

A

One of the Ubs has a Ile44 patch and the other had a Ile36 patch at the interface (where they join)
Closed conformation

37
Q

Give the structure of Lys11-linked diubiquitin

A

Has two Ile36 patches at the interface

Closed conformation

38
Q

Give the structure of Lys48-linked diubiquitin

A

Has two Ile44 patches at the interface

Closed conformation

39
Q

Give the structure of Met1 and Lys63-linked diubiquitins

A

Open conformation

40
Q

Name the UBDs which recognise Ile44 patches in monoUb

A 
Ub interaction motif (UIM) 
MIU (Motif interaction Ub) - reverse of UIM 
CUE 
GAT 
UBA
41
Q

Name a UBD which doesn’t always bind to Ile44

A

zinc finger UBDs

42
Q

What are the types of Zinc finger UBDs? And what do they bind

A

UVZ - recognises Ile44 patch

IsoT - recognises Ile36 and the C-terminal tail of Ub

43
Q

What is special about IsoT?

A

Since it can bind to the C-terminal tail of Ub, it can bind to free Lys76 - important in Ub chains which have been cleaved and released and need to be broken down

44
Q

Name a UBD which recognises polyUb chains

45
Q

Describe Rap80

A

it has 2 UIM motifs which occur in tandem
Each recognise Ile44 patches of one Ub
It only binds to polyUb which are K63 linked

46
Q

Why does Rap80 only recognised K63 linked polyUb?

A

Due to the linker which seperates the 2 UIM

47
Q

Name 2 single UBDs which can recognise 2 Ubs

A

TAB2 ZNF

hHR23 UBA

48
Q

Describe TAB2 ZNF

A

Found on the TAB2 protein
Binds K63 linked polyUb
Has two interfaces which both recognise a Ile44 patches

49
Q

What is TAB2?

A

Part of the PAK1 complex involved in NF-kappaB signalling

50
Q

Describe hHR23 UBA

A

Found on hHR23
Recognises K48 chains - targets them for degradation by the proteasome
Has 2 interfaces

51
Q

How is ZNF able to bind to K63?

A

Change it to a closed conformation from an open one

52
Q

Name a UBD which recognises PolyUb Met1

53
Q

What are the 3 classes of Ub ligase?

A

RING
HECT E3 ligase
RER

54
Q

What is a RING Ub ligase?

A

A substrate and a charged E2

Gets a direct transfer of Ub onto the substrate

55
Q

What is a HECT E3 ligase?

A

Accept a charged Ub from a charged E2 ligase and passes it onto the lysine of the substrate

56
Q

What is an RER Ub ligase?

A

Hybrid of a RING and HECT E3 ligase

57
Q

How does HECT E3 ligases work?

A

A charged E2 entraps the HECT E3 ligase -> Ub is transferred onto a cysteine-kappa-cysteine of the HECT -> Ub is transferred onto a Lys of the substrate

58
Q

How are proteins targeted for degradation?

A

UBE2C will add a single Ub onto the substrate (priming) and then goes away -> UBE2S will then add more Ub onto the initial substrate (elongation) - causes branched chains

59
Q

Which chains are better for degradation?

A

Branched (K48 linked with more than 4 Ub)

60
Q

What are homotypic chains better for?

A

Signalling

61
Q

Why is protein degradation important?

A

Protein aggregates are a marker of neurodegenerative diseases such as Huntington’s, Parkinson’s and Alzheimers

62
Q

What are the 2 subunits of the proteasome?

A

a 19S regulatory particle and a 20S co-particle

63
Q

What is the function of the co-particle

A

To chop up the proteins by the 3 different proteolytic sites it contains

64
Q

Why are large protein aggregates not targeted by the proteasome?

A

Since they have large globular heads

65
Q

How does the proteasome work?

A

RP is the lid and has receptors which bind to the Ub chains -> Proteins enter as folded proteins -> ATPase pulls it through -> it unfolds as it enters the CP

Advanced Cell Signalling (12 decks)

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