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Endo and cell signalling > Proteoglycans, glycosaminoglycans, fibroblast growth factor signalling > Flashcards

Proteoglycans, glycosaminoglycans, fibroblast growth factor signalling Flashcards

1
Q

FGF signalling complexes are a _____ complex involving

___:____:__

A

ternary complex

FGF:FGFR:HS

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2
Q

What are proteoglycans?

A

Heavily glycosylated,
specialised glycoproteins
They have a protein core with one or more attached glycosaminoglycan polysaccharide chains

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3
Q

Where are proteoglycans located?

A

On the cell surface matrix (surrounding virtually all mammalian cells)

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4
Q

What synthesises the proteoglycan protein core?

Where is it translocated to?

A

Ribosomes

Translocated to the rough ER

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5
Q

Give some functions of proteoglycans (5)

A
  • Regulate and modulate protein functions
    (which depends on the conformation of the glycosaminoglycan chain)
  • Part of the extracellular matrix
  • Stabilise proteins and protein complexes
  • Sequester cations
  • Complex with H20
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6
Q

What is

Mucopolysaccharidoses

A

Genetic disorders causing abnormal activity of lysosomal enzymes responsible for GAG degredation.
Causes accumulation of PGs in cells

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7
Q

Give 2 cell surface proteoglycans

1 is transmembrane and 1 is GPI anchored

A

Syndecans (transmembrane)

Glycipans (GPI anchored)

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8
Q

What is the motif for GAG chain attachment to the protein core

A

-Ser-Gly-X-Gly-

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9
Q

What is the haparin/HS GAG motif?

A

tetrasaccharide linker region–Xyl-Gal-Gal-GlcA

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10
Q

What are the transferases that attach the GAG chain to the serine residues on the protein core?

A

Xylosyltransferase (for Xyl)

Galactosyltransferase I and II (for Gal 1 and 2)

Glucuronosyltransferase I (GlcA)

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11
Q

GlcA =
IdoA =
Gal =

A 
GlcA = Glucuronic acid
IdoA = Iduronic acid 
Gal = Galactose
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12
Q
  • GalNAc =
  • GlcNAc =
  • GlcNS =
A 
• GalNAc =
 N-acetylgalactosamine 
• GlcNAc = 
N-acetylglucosamine 
• GlcNS = 
N-sulfoglucosamine
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13
Q

(xS) =

A

sulphate group and its position (x)

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14
Q

What is the net charge on Glycosaminoglycans?

A

Negative

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15
Q

What is the prepeating disaccharide unit on Glycosaminoglycans?

A

{hexose/hexuronic acid – hexosamine}n

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16
Q

Where does the variation between composition of the GAG chains for different family members occur?

A

The linkage between and within the repeating disaccharide unit
Heparin and HeparanS both have 1-4 linkage intra and inter repeats

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17
Q

What is the simplest form of the repeating unit for heparin and heparan sulphate composition?

A

—– 4 Uronic acid 1 —-

4 glucosamine 1 ——

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18
Q

Uronic acids:

How does Glucuronic acid (GlcA) –> Iduronic acid (IdoA)

A

C-5 Epimerase

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19
Q

The glucosamine residue can be derivatised to:

A

N-acetylglucosamine (GlcNAc)
or
Sulphoglucosamine (GlcNS)

(both can be O-sulphated)

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20
Q 
Heparin :
>Comprised of a \_\_\_ acid linked to a \_\_\_\_ repeating unit 
>Common repeat unit is
\_\_\_\_\_\_\_
>Highly \_\_\_\_\_\_\_
>Important clinically as \_\_\_\_\_\_
A

Heparin
Comprised of a uronic acid linked to a glucosamine repeating unit
Common repeat unit is IdoA(2S)-GlcNS(6S)
Highly sulphated
Important clinically as an anticoagulant

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21
Q

Heparan Sulphate:
>Contains a ___ structure
>Expressed (by almost all mammalian cells)strategically on ____ and in the _____
>Highly complex _____ mechanism which is tightly regulated
Common biosynthesis with ___

A

Highly complex sulphated polysaccharide
Contains a domain structure
Expressed (by almost all mammalian cells)strategically on cell surfaces and in the extracellular matrix
Highly complex biosynthetic mechanism which is tightly regulated
Common biosynthesis with heparin

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22
Q

What are the UDP attached building blocks of HS and how are they first joined?

A

UDP-GlcNAc
(N-acetylglucosamine)
UDP-GlcA
(Glucuronic acid)

HS copolymerases (EXT1-2, EXTL1-4)

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23
Q

Describe the sulphation pattern of:
Heparan sulphate
and Heparin

A

HS = Sulphation pattern is organised into structured domains and is tissue specific and therefore very scarce

Heparin = Sulphation pattern is homogeneous and more heavy than HS
High quantities can be derived from porcine intestinal mucosa or bovine lung

24
Q

Heparin:
Used clinically as an ____
Found only in the secretary granules of _____

A

anticoagulant

mast cells

25
Q

Give some functions of HS

A 
• Growth factors 
• Cytokines 
• Extra-cellular matrix components 
• Pathogen adhesion 
• Heparan sulphate has been shown to influence cell proliferation, 
migration and differentiation
26
Q

What are 4 common HS protein interactions?

A
  • Conformational activation
  • Enhancing protein-protein interactions (e.g. thrombin with ATIII)
  • Co-receptor for extracellular ligands (e.g. HSPG coreceptor for FGF ligand)
  • Cell surface localisation
27
Q

Give 6 types of proteins that HS has been demonstrated to affect the biological activity.

A
  • Growth factors (such as FGFs)
  • Cytokines (e.g. Interferons)
  • Enzymes (lipoprotein lipase)
  • ECM proteins (e.g. collagen)
  • Protease inhibitors
  • Coagulation factors (e.g. antithrombin)
28
Q

What are fibroblast growth factors and their functions?

A

-Extracellular animal proteins
(Needed for homoeostasis and development for almost every tissue in the human body)
– Control cell proliferation, differentiation, migration & survival
– Modulate development
– Promote angiogenesis
– Encourage wound repair

29
Q

How many FGF family members are there?

A

22

30
Q

What are FGF-1 and FGF-2 also known as?

A

FGF-1, also known as acidic FGF, (can signal though all FGFRs that have the capacity for intracellular signalling )

FGF-2 is known as basic FGF

31
Q

What is FGF4 involved in?

How is it mediated?

What does the glycosylation site do

A

FGF-4 is developmentally expressed
– Involved in the formation of multiple tissues
– Crucial role in the inner cell mass of the early embryo

– Function is predominantly mediated through cell surface receptors

– FGF-4 contains a protein glycosylation site is thought to down-regulate FGF-4activity

32
Q

When and where is FGF-6 expressed?

A

Post natal, expression in the adult skeleton

33
Q 
What are the roles of:
FGF-7
FGF-8
FGF-9
FGF-10
A

FGF-7: Signicalling in epithelial cells

FGF-8: Required for gut formation

FGF-9: Neuronal functions

FGF-10: Required for lung formation

34
Q

How many FGF receptors are there and which ones bind to Hep/HS

A

5

1-4 bind

35
Q

Which FGF is the universal ligand?

A

FGF-1

activates all FGFR’s

36
Q

What is the FGFR domain structure starting with the intracellular C-tail

A 
Intracellular C tail
Split Tyrosine kinase domain
===Juxtamembrane region===
2 Ig loops (D2 and D3)
Acid box
D1 Ig loop
37
Q

What is the role of the Ig1 FGF domain

A

Not involved in binding
Deletion promotes FGF binding
(inhibitory domain)

38
Q

What is the role of the extracellular acid box?

A

Contains amino acid residues

Interacts with D2 to inhibit HS binding

39
Q

Which FGF domains are involved with FGF binding

Which is involved with HS binding

Which dictates FGF specificity?

A

FGF - Ig2 and Ig3

HS - Ig2(D2)

D3/Ig3 dictates specificity

40
Q

FGFR’s:

  • Alternate mRNA splicing gives rise to more ____
  • commonly __ signalling variants
  • _______ determines signalling type and outcome
A

Alternate mRNA splicing gives rise to more variants

commonly 7 signalling variants

FGF:FGFR pairing determines signalling type and outcome

41
Q

What other extracellular molecules can regulate FGFR signalling?

A

e.g. Anosmin-1, E-Selectin, Neuropilin-1 and Cadherins

42
Q

What are the roles of the proteins that regulate FGFR signalling:

A

– E-selectin (binds FGFs, effect unknown)
– Cadherins (bind FGFR and signal through these)
– Neuropilin-1 (increases cell growth responses)
– Anosmin-1 (altered cell growth responses)

43
Q

HS is necessary for FGF to deliver a ________

A

growth-promoting signal

44
Q

FGFRs signal differently in the presence or absence of HS.
• Signalling is different in terms of:
_____ +
______

A

kinetics

cell fate they stimulate the cell to adopt.

45
Q

HS induces ______ of FGF and interacts with FGFR
to form a _______ .

This causes ______ of TK domains and sustained activation of intracellular ______

A

HS induces dimerisation of FGF and interacts with FGFR to form a high affinity ternary complex.

This causes autophosphorylation of TK domains and sustained activation of intracellular signalling cascade.

46
Q

What are the 3 hypothesis/models for FGFR signalling?

A

Conformational change
Growth hormone
Ligand-induced dimerisation
(must look at these before exam)

47
Q

What are the 2 models for ligand-induced dimerisation?

A 
Pellegrini model (2:1:2) 
Schlessinger model (2:2:2)
48
Q

What is Kallmann Syndrome?

A

Human disorder due to abnormalities of development of specific neurons
– olfactory neurons
– gonadotropin-releasing hormone-1 (GnRH-1) neurons

49
Q

What are the modes of inheritance for Kallmann Syndrome?

A

X-linked and autosomal dominant modes of inheritance

50
Q

What are the genes indentified to be responsible for Kallmann Syndrome and what proteins do they affect?

A

– KAL-1 : (X linked) → Anosmin-1

– KAL-2 : (Autosomal dominant) → FGFR1

51
Q

What are some symptoms of Kallmann syndrome?

A
  • Olfactory bulb dysgenesis → Anosmia (inability to smell)
  • Hypogonadotrophic hypogonadism (GnRH deficiency causing growth deficiency)
  • Bimanual synkinesis (mirror image upper body movements)
  • Bi- and uni-lateral renal agenesis
  • Genital defects
  • Midline defects (cleft palate and lip)
52
Q

How many males and females does Kallmann Syndrome affect?

A

Affects 1 in 8,000 males and 1 in 40,000 females

53
Q

What is Anosmin-1?

Where is it expressed?

A

> Heparin/HS binding protein (5 putative HS binding sites)
Secreted, extracellular matrix associated, glycosylated protein
Expressed in developing brain, olfactory bulb, spinal cord & kidney

54
Q

What does Anosmin do to FGFR1?

A

Anosmin amplifies FGFR1 signalling response

55
Q

Anosmin can bind to ____ and _____

• Anosmin cannot bind to ____ or _____

A

Anosmin can bind to FGFR1 and HS

• Anosmin cannot bind to FGF-2 or FGF-2:HS

56
Q

If Anosmin is bound to ___ or ____
complex cannot bind
→ signalling is not stimulated via _______

A

If Anosmin is bound to FGFR1, FGF-2:HS
complex cannot bind
→ signalling is not stimulated via receptor
dimerisation

57
Q

If Anosmin is pre-bound to ____, it can form

an active complex with FGF2-FGFR1

A

If Anosmin is pre-bound to HS, it can form

an active complex with FGF2-FGFR1

Endo and cell signalling (12 decks)

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