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BIOL301 Cell Signalling > Lecture 7: TGF-beta > Flashcards

Lecture 7: TGF-beta Flashcards

1
Q

How many isoforms of TGF-beta do humans have?

A

3

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2
Q

What other cytokines are part of the same superfamily as the TGF-betas?

A

Activins
Nodals
Bone Morphogenic Proteins (BMPs)

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3
Q

What does it mean that TGF-beta cytokines are pleiotropic?

A

has activity in multiple cell types - mainly inhibits proliferation by cell cycle arrest but also controls wound healing, ECM formation, apoptosis, differentiation and immunosuppression

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4
Q

True or False: there is structural homology between ligands and receptors in the TGF-beta cytokine superfamily?

A

True

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5
Q

Describe the distribution of TGF-beta expression?

A

It is ubiquitous - one or more isoforms are expressed by most cells

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6
Q

Describe the production and storage of TGF-beta

A

Synthesised as an inactive precursor proteins that binds to ECM components and is sequestered in the ECM

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7
Q

Describe the structure of the TGF-beta precursor protein

A

Has two distinct domains:
- prodomain (latency-associated peptide/LAP)
- TGF-beta domain

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8
Q

Describe the production of inactive TGF-beta

A
  • proteolytic cleavage of the LAP pro-domain by serine proteases such as furin
  • the two domains remain associated by electrostatic interaction between the LSKL sequence of the LAP domain and the RKPK sequence of the TGF-beta domain
  • Disulfide bridges form dimers between two LAP domains and two TGF-beta domains
  • Latent TGF-beta binding protein / LTBP binds the inactive complex that is then secreted and stored as reservoir in ECM
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9
Q

Following proteolytic cleavage of the LAP pro-domain, what holds the two domains together?

A

electrostatic interaction between the LSKL sequence of the LAP domain and the RKPK sequence of the TGF-beta domain

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10
Q

Describe the activation of TGF-beta

A
  • TSP-1 outcompetes TGF-beta for binding to the LSKL sequence of LAP causing the LAP dimer to dissociate from the TGF-beta dimer
  • Serine proteases digest the LAP domain
  • this results in active TGF-beta homodimers/heterodimers (and tetramers) that gives a range of signalling diversity.
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11
Q

Describe the structure of a TGF-beta dimer

A

Each monomer has two finger turn antiparallel beta sheet domains that interact with the receptor and a short alpha helix
- each monomer is stabilised by a cysteine knot
- the dimer is held together by a disulphide bridge between the two monomers

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12
Q

why is a cysteine knot so stable?

A

It is formed of three disulphide bridges

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13
Q

How many TGF-beta receptors are there?

A

3

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14
Q

How many variants of the TGF-beta RI and TGF-beta RII are there?

A

7 TGF-beta RI variants

5 TGF-beta RII variants

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15
Q

Describe the TGF-beta RI receptor

A
  • transmembrane
  • homodimeric
  • Ser/Thr kinase activity inactive until TGF-beta binds
  • the cytosolic domain determines the specificity of response by binding to a range of intracellular proteins
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16
Q

Describe the TGF-beta RII receptor

A
  • Transmembrane
  • homodimeric
  • constitutively active ser/thr kinase activity
  • binds the TGF-beta ligand
17
Q

Which TGF-beta isoforms does TGF-beta RII bind with high affinity?

A

1 and 3

18
Q

What is the difference between the ser/thr kinase activity of the TGF-beta RI and RII?

A

The RII kinase activity in constitutively active

where as the RI kinase activity is only active when TGF-beta is bound

19
Q

Which TGF-beta receptor is responsible for signal transduction?

A

TGF-beta RI

20
Q

Which TGF-beta receptor is required for TGF-beta 2 signalling?

A

TGF-beta RIII
- increases local concentration of TGF-beta 2 for binding to TGF-beta RII (may even change configuration of TGF-beta RII to increase binding to TGF-beta 2 ligand)

21
Q

Describe the binding of a TGF-beta dimer to its receptor (RI and RII)

A
  • TGF-beta dimer binds to RII dimer
  • Stimulates recruitment of RI dimer to the complex
  • Kinase activity of RII transphosphorylates RI dimer on ser/thr in GS (Gly/Ser rich) domain
  • results in conformational change in RI, which displaces the immunophilin FKBP12 (inhibitor of RI) - FKBP12 binds to unphosphorylated GS domains and stabilises the inactive RI conformation
22
Q
A

BIOL301 Cell Signalling (10 decks)

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