Transcript Graves` Disease Case: Previously

Graves’ Disease Case: Previously
Normal thyroid signaling requires circuit of signaling:
hypothalamus, pituitary, thyroid
Signaling between cells requires signals and receptors
5 types of extracellular signals
4 classes of receptors
Hypotheses about root problem in Graves’ disease
Thyroid overstimulated (too much TSH or works ‘too well’)
External signals ‘normal’ but response in thyroid not
appropriate
Testing the hypotheses
IF hypothesis is true then what is expected?
What data would suggest the hypothesis
needs to be revised?
Hypothesis : Thyroid being over-stimulated
Known: Normal stimulation results from TSH/receptor
interaction
How does the thyroid ‘know’ to react?
How does a receptor provide specificity?
Protein structure
Amino acid sequence and folding environment
determine the conformation of a protein
Parts of a protein: amino acids
Amino acids: 5 characteristic parts
If all proteins made of amino acids and all amino
acids have the same parts why do proteins do
different things?
Side chains hold the ‘information’
Conventions for writing and speaking about proteins:
The N and C termini
Polarity of proteins
Levels of Protein Structure
Primary Structure
Secondary Structure
Adapted from: http://www.bmb.psu.edu/courses/bisci004a/chem/profold.jpg Benjamin Cummings. Ltd. 2001
Levels of Protein Structure
Tertiary Structure:
Quaternary structure
Protein Kinase C Interacting Protein. http://lectures.molgen.mpg.de/ProteinStructure/Levels/quaternary.gif
TSH Receptor: What level of structure?
Extracellular
Plasma membrane
Cytosolic
TSH Receptor: from “The Thyroid Manager” Ch16
Can we predict protein structure?
Motifs and Domains
How do you change a protein’s shape?
Alter the chain
Change the environment–
what it is floating in or binding with
Possible reasons for Graves’?
The players:
hormones (4)
receptors (4 ‘major’)
Positive interactions and
negative feedback
Graves’ hypothesis 1: TSH, TSH-Receptor
interaction ‘too strong’
According to this hypothesis and what we
now know about protein binding
T3 and T4 levels should be ____ in Graves’
vs. normal.
TSH levels should be _____ in Graves’ vs.
normal
TSH/TSH receptor interactions should show
______ binding constant vs. normal.
Blood tests show
T3 and T4 levels are elevated
TSH levels are decreased
TSH/TSH receptor interactions have same
binding constant vs. normal.
Therefore: Perfectly logical hypothesis…….
Not supported by data
Now what?
Hypothesis 2: Mutation in signaling within
cell leading to increase in thyroid hormone
production
Normal activation is the result of signal
transduction second messenger cascade
How does signal transduction work?
What could have gone wrong?