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kris Endocrinology > 2 > Flashcards

2 Flashcards

1
Q

What are receptors made of?

A

proteins

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2
Q

Since receptors are proteins, do ligands have to be proteins as well?

A

no

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3
Q

When is a protein said to be a target protein

A

when it’s activation results in a change in a cell- function, status, gene expression or shape

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4
Q

How many signalling proteins interact with target proteins?

A

one or more

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5
Q

What does a reaction cascade lead to?

A

the cascade leading to activation/ inhibition of target protein can either come as modification or interaction with the protein
once target protein is acted upon, this often leads to a feedback reaction that ges to the beginning of the signal
the receptors are often inhibited either by internalization or a change in the shape of the receptor
thus a signal not only acts on a target receptor but on a receptor itself

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6
Q

What are the 2 main classes of signal receptor pathways? What do they depend on?

A
  • Pathways with cell-surface receptors- hydrophilic signal molecule + cell surface receptor
  • Pathways with intracellular receptors- hydrophobic signal molecule + intracellular receptor
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7
Q

How many domains dose a cell surface receptor have? WHat are they and their functions?

A

3 domains

  • extracellular domain which interacts with the signal
  • cytoplasmic domain is the one that initiate the change inside the cell
  • the portion within the bilipid bilayer is the transmembrane domain
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8
Q

Describe structure of transmembrane domain

A
  • as the lipid biayer is lipid, the transmembrane portion is made of hydrophobic AA
    each pass through the membrane is usually 20-24 AA in length- has several passes
    hydrophobic AA that form transmembrane domain are called a-helixes
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9
Q

Describe structure of extracellular domain

A
  • extracellular domain typically has disulphide bonds and CHO attachments that give it 3d structure to which hormones can come and interact
  • extracellular domain is made of nitrogenous end which contains more cysteine which harbours disulphide binds
  • disulphide bonds confer 3d structure and are also often glycosylated
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10
Q

Which domain contains disulphide bonds?

A

extracellular

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11
Q

Describe structure of cytoplasmic domain

A

made of COOH end of the protein

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12
Q

Are domains of receptors dependent on each other?

A

domains have modular nature- different domain form different receptors can be mis-matched-> domains can function independently from each other

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13
Q

Which protein end does signal bind to

A

Signal binds to ectodomain (NH2 end)

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14
Q

What are the potential problems of ectodomain-only receptors?

A

many receptors have isoforms that are purely made of extracellular domain which are directly released to the outside the cells
sometimes act as buffer systems for hormones, sometimes they don’t
e.g. GH has an isoform that has just the extracellular domain and acts as a buffer which increases the half-life of GH

sometimes this domain can stimulate antibody production which can end up at cell surface receptor and activate it.
This transmembrane receptor becomes active, leading to a continuous signal transduction
e.g. antibodies free extracellular domain for TSH receptor
releases TSH receptor stimulates antibody production which binds to THS receptor and stimulates thyroid gland-> hyperthyroidism-> Graves disease with increased thyroid hormone concentration-> goiter

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15
Q

What is the 1st step of the cascade?

A

the cytoplasmic domain, activated by conformational changes, induces a signalling cascade

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16
Q

what are conformational changes of the cytoplasmic domain induced by

A
  • Phosphorylation of proteins

- Binding between proteins

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17
Q

Where and how does phosphorylation occur?

A

common post-translation modification is phosphorylation which typically occurs on the following AA: serine, threonine and tyrosine
Steps:
hydroxyl group is removed, phosphate group is added
phosphate group comes from ATP

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18
Q

What does phosphorylation of a protein result in?

A

in the conformational change of the protein

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19
Q

Does phosphorylation result in activation or deactivation?

A

Can lead to both

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20
Q

What is the function of phosphatases?

A

reverse phosphorylation (dephosphorylate)

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21
Q

Which AA out of 3 that get phosphorylated are more common?

A

Phosphorylated serines and threonines more abundant than phosphorylated tyrosines

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22
Q

Phosphorylation of which AA is usually the beginning of phosphorylation cascade?

A

Tyrosines phosphorylation often occurs at the beginning of a cascade (many receptors have or induce tyrosine kinase activity)

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23
Q

What do phosphorylated tyrosines usually act as?

A

The phosphorylated tyrosines serve as docking sites for down stream signal proteins- locking other protein at a phosphorylation site, keeping it activated

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24
Q

What are SH2 and SH3 domains?

A

The amino acid sequence that mediates docking to phosphorylated tyrosines (SH2 and SH3 domains) is conserved and diagnostic for proteins involved in the signaling cascade
SH2 domains allow proteins containing those domains to dock to phosphorylated tyrosine residues on other proteins. SH2 domains are commonly found in adaptor proteins that aid in the signal transduction of receptor tyrosine kinase pathways.
The classical SH3 domain is usually found in proteins that interact with other proteins and mediate assembly of specific protein complexes

25
Q

What are the 3 major types of cell surface receptors?

A

1) Tyrosine kinase linked
i) Intrinsik TK activity- receptors themselves have enzymatic capability to phosphorylate tyrosine
ii) rectuited TK activity- recruit tyrosine kinase for phosphorylation to occur
2) G-protein coupled receptors

26
Q

Which part of protein moves away after ligand binding? Why does it move away

A

G- alpha

Usually moves away to go on and activate an enzyme

27
Q

Describe different types of G-alpha subunits

A
  • Gs⍺ alpha: Activates adenylate cyclase- > uses cyclic AMP to activate PKA-> cascade reaction
  • Gi⍺ alpha: Inhibits adenylate cyclase
  • Gq⍺ alpha: Activates phospholipase C-> IP3 and DAG and Ca signaling
  • Go⍺ alpha: Activates ion channels
  • G12/13⍺: regulate Actin cytoskeleton-> G12/12a brings about a change in cell shape/movement of the cell
28
Q

What is the most common type of cell surface receptros

A

g-protein

29
Q

How many alpha-helixes form a pore of a g-protein receptors?

A

7 alpha- helix loops

30
Q

Do endocrine signals or non-endocrine signals use G-protein receptors?

A

Both

  • Many receptors of non-endocrine signals also act via G-proteins. Examples: glutamate (neurotransmitter), thrombin, odorants and photoreceptors
  • Examples of endocrine hormone receptors are TRH, GnRH, TSH, LH, FSH, ACTH, GHRH and oxytocin
31
Q

Do hormones only use one type of G-proteins

A

can use more than one

32
Q

Is the type of g-protein used by the signalling molecule always constant?

A

G protein use may change during development

G protein use may change depending on the hormone concentration or in different tissues

33
Q

Example of intrinsic TK receptor

A

insulin

34
Q

Describe the structure of intrinsic TK receptors

A

has 2 domains- alpha and beta
alpha and beta are expressed by the same gene that has 3 portions: a, b , c
during post translation modification, c is cleaved off; a and b are joined by S-S bonds
b is transmembrane domain part

35
Q

Which post-translation process does insulin receptor undergo?

A

Formation of disulfide bonds and proteolytic cleavage

36
Q

Where is the highest concentration of insulin receptors found? Why?

A

highest in adipocytes and hepatocytes as these tissues are involved in glucose processing the most

37
Q

Sequence of events after insulin binding

A

1) insulin binding to the receptor
2) Autophosphorylation of intracellular domain of receptor via intrinsic TK activity
3) Docking (recruitment) and phosphorylation of IRS-1 and IRS-2 (insulin receptor substrate)- dimerization
4) Activation of two major signal pathways- either MAPK or PI3 pathway

38
Q

Insulin is similar to which hormone?

A

IGF-1

39
Q

Insulin Receptor Signalling through MAPK pathway

A

1) insulin binds to it’s receptor and undergoes autophosphorylation on its carboxyl-terminal Tyr residues
2) Insulin receptor phosphorylates IRS-1
3) Grb2 binds to IRS-1 and SOS binds to GRB2, causing GDP release and GTP binding to Ras
4) Activated raf binds and activates Raf-1
5) Raf-1 phosphorylates MEK on 2 Ser residues, activating it. MEK phosphorylates ERK
6) ERK moves into the nucleus and phosphorylates nuclear transcription factors such as Elk1, activating them
7) Phosphorylated Elk1 joins SRF to stimulate the transcription and translation of a set of genes needed for cell division

40
Q

What are Raf and Ras and when do they get activated?

A

Ras and Raf are enzymes which can act as kinases

activated when GDP is replaced with GTP

41
Q

What are Grb2 and SOS

A

adaptor proteins

42
Q

What are MEC and ERK

A

MEC and ERK are serine-threonine phosphorylases

spread the signal as they have multiple target- cytoplasmic protein or nuclear proteins

43
Q

Which residues are phosphorylated in insulin receptor MAPK pathway

A

tyrosine residues, until Raf-1
Raf-1 phosphorylates Ser residues
MEK and ERK phosphorylate serine and threonine

44
Q

Which protein is responsible for spreading the signal and entering the nucleus on MAPK pathway?

A

Phosphorylated Elk1

45
Q

nsulin Receptor Signalling through PIP3

A

1) Irs-1 phosphorylates by insulin receptor activates PI3 kinase
2) PI3K phosphorylates a lipid by converting IP2 to IP3
3) PKB binds to PIP3 and begins PIP3 pathway

46
Q

How does GSK3 act

A

Phosphorylated GsK3 is inactive
Not phosphorylated active GSK3 inactivates glycogen synthase (GS) by phosphorylating it
Active GS and NOT phosphorylated results in glycogen synthesis

47
Q

How does PKB helps insulin depended glycogen synthesis process

A

brings glucose transporters to the cell surface

48
Q

What are receptors with recruited tyrosine kinase activity characterized by

A

Characterized by 4 alpha-helices and homology of the ectodomain (hormone binding site)

49
Q

What are receptors with recruited tyrosine kinase activity known for?

A

Best known are the receptors for growth hormone (GH), prolactin (PRL) and leptin

50
Q

Receptors with recruited tyrosine kinase activity are a group of __/__ receptors

A

Receptors with recruited tyrosine kinase activity are a group of cytokine/haemopoietic receptors

51
Q

Describe GH signalling pathway

A

1) GH has two binding sites and binds sequentially to two receptor molecules-> thus requires 2 receptors per molecule-> dimerization
2) Binds to 1 receptor first, which brings in 2nd receptor-> Dimerization of the cytoplasmic regions initiates signal transduction, by recruiting JAK-2 kinase

52
Q

WHat initiate GH signalling pathway cascade?

A

JAK2 recruitment initiates phosphorylation cascade

53
Q

What does JAK2 phosphorylate?

A

phosphorylates itself, the receptor and other proteins

54
Q

What are the 3 branched of GH signalling pathways

A
  • Branch 1: Activation of the transcription regulatory proteins, STAT, which are transcription factors (4 isoforms), found in the cytoplasm and move to the nucleus when activated
  • Branch 2: Activation of the MAPK pathway (as insulin, but JAK2 plays the role of IRS1)
  • Branch 3: Activation of PI3K pathway
55
Q

Jak-stat pathway

A

1) after JAK is recruited and dimerization occurred,
tyrosine kinase activity is stimulated
2) they phosphorylate themselves and phosphorylate the receptors
3) this phosphorylation of the receptor’s cytoplasmic domain allows for recruitment of STAT (has 4 isoforms)
4) Stat is brought to the receptor
5) JAK-2 phosphorylates STAT
6) Phosphorylated STAT dimerize and are released from the receptor and go into the nucleus
7) Bind to DNA and effect gene expression as STATs are TF

56
Q

Which pathways can G-protein can participate in?

A

Adenylyl cyclase

Phospholipase C

57
Q

Which pathways can initiate MAPK or IP3 cascades?

A

IRS-1 or Jak-2

58
Q

What is the length and the AA components of transmembrane domainÉ

A

20-25 a.a. needed to

cross membrane once (Ala, Ile, Leu, Met, Phe, Val, Pro, Gly)

kris Endocrinology (17 decks)

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