Powerpoint 3 Flashcards
What are the two main receptor pathways of cells?
- Pathways with CELL SURFACE receptors
2. Pathways with INTRACELLULAR receptors
In terms of cell surface receptors, what area does the signal bind to? What terminus of the protein receptor molecule is extracellular and the signal binds to?
- ectodomain
2. N - terminus
What amino acid is ectodomain part of the protein receptor rich in?
cysteine residues - S-S bonds for folding - often glycosylated
What shape is the hydrophobic transmembrane domain? How many amino acids are needed to cross the membrane?
alpha-helix
25
The ectodomain, the hydrophobic transmembrane domain, and the cytoplasmic domain are functionally _______ and ________.
- independent
2. interchangeable
Free ectodomain may circulate as what?
hormone binding protein
What are two examples of ectodomains that act as hormone binding proteins?
- The GH receptor ectodomain acts as a GH binding protein in the blood circulation
- The ectodomain cleaved from the TSH receptor may induce antibodies which bind to the receptor and mimic TSH action
What is the cause of hyperthyroidism in Grave’s disease?
The ectodomain cleaved from the TSH receptor induces antibodies which bind to the receptor and mimic TSH action
What is hyperthyroidism?
an overproduction of thyroid hormone which causes enlargement of the thyroid + expo thalamus (bulging eyes), heat intolerance, and anxiety
How does the cytoplasmic domain induce the signal to the interior of the cell?
signalling cascade vis phosphorylation of proteins and binding between proteins
Many signalling proteins are activated by phosphorylation of what 3 amino acids? What is the phosphate donor?
Serine, threonine, tyrosine. All have a polar hydroxyl that gets replaced by a phosphate group
ATP
Phosphorylation of serine, threonine, and tyrosine causes what to the protein?
conformational change
Many signalling proteins are ______ that are activated by ________.
Kinases
Phosphorylation
Phosphorylation can be reversed by what enzyme?
phosphatases
What are 3 advantages of phosphorylation of proteins as a controlling mechanism for signal transduction?
- Rapid (does not require new protein synthesis or degradation)
- Reversible (easily reversed via protein phosphatases)
- Easy to relay signals (phosphorylation on Try, The, or Ser creating binding sites for other proteins
__% of all cellular proteins are phosphorylated
10
Out of Serine, threonine, and tyrosine, which of the 3 are the most abundant? What ratio?
serine + threonine : tyrosine
100 : 1
Why is the phosphorylation of tyrosine special?
because it occurs at the beginning of a signal cascade
What do the intracellular domains of many receptors have/induce? How is this activated?
Tyrosine kinase activity - activated by hormone binding to receptor
What do phosphorylated tyrosine act as?
docking sites for downstream signal proteins
What are the amino acid sequences called that mediate docking to phosphorylated tyrosine?
SH2 & SH3
What are the 3 major types of cell surface receptors?
- Receptors with intrinsic tyrosine kinase activity
- Receptors with recruited tyrosine kinase activity
- G-protein coupled receptors
How many times does the peptide chain cross the cell membrane in tyrosine kinase coupled cell surface receptors?
1 time
What is the structure of the insulin receptor?
Hetero-tetrameric structure: 2 alpha & 2 beta chains held together by disulphide bonds
How many insulin receptors can be found per cell? What cell types have the highest amount?
100 to 200,000
Highest in adipocytes and hepatocytes
What receptor is very similar to the insulin receptor?
the receptor for the IGF-I hormone
Insuline converts excess blood glucose into what 2 storage forms?
- glycogen in liver and muscle
2. tiacylglycerols in adipose tissue
What do defects in the insulin receptor/signalling pathway lead to? How many mutants have been identified in the insulin receptor alone?
insulin resistance syndroms
> 50
What are the 2 symptoms associated with insulin resistance syndromes due to defects in the insulin receptor/signalling pathway?
- impaired glucose metabolism
2. raised insulin concentrations
What are the 3 insulin resistance syndromes?
- Type A insulin resistance (mild)
- Rabson-Mendenhall syndrome (medium) - receptor partially functioning
- Leprechaunish/Donahues syndrome (severe) - severe intra uterine growth retardation - most patients dead < 1 year
What are receptors with recruited tyrosine kinase activity characterized by?
4 alpha-helices and homology (symmetry) of the ectodomain
Receptors with recruited tyrosine kinase activity are found on what type of cells?
cytokine(immune system cells)/haemopoietic(tissues that give rise to blood cells)
What are the 3 most popular receptors with recruited tyrosine kinase activity?
- receptor for GH
- receptor for prolactin (PRL) - stimulates milk production after child birth
- Receptor for leptin - regulates fat storage in body
How many binding sites does the GH receptor have?
2 - binds sequentially to two receptor molecules
What stimulates signal transduction in GH and PRL signalling pathways?
dimerization of the cytoplasmic regions
Which two hormones cause a homodimer formation in the cytoplasmic membrane?
PRL & erythropoietin
What type of dimers do hormones that bind to receptors with recruited tyrosine kinase activity form?
heterodimers and oligomers
What are the 3 branches of the signalling pathway of GH?
First JAK2 kinase is activated and phosphorylates itself, the cytoplasmic domain of the receptor and other proteins.
Branch 1: Activation of the transcription regulatory proteins STAT (4 different proteins)
Branch 2: Activation of the MAPK pathway (as insulin, but not dependent on IRS1)
Branch 3: Activation of PI 3-kinase pathway (as insulin). Responsible for insulin-like metabolic effects of GH.
What does STAT stand for?
Signal Transduction and Activation of Transcription
What syndrome results from a defective GH receptor?
Laron syndrome (dwarfism) - severely impaired growth but normal or elevated levels of GH
How many exons do GH receptors contain? Large deletions in what specific exons were found in two Laron sydrome patients?
10 exons
3, 5, 6 (part of signal peptide and ectodomain)
