Graves’ Disease Case: PreviouslyNormal thyroid signaling requires circuit of signaling:

hypothalamus, pituitary, thyroid

Signaling between cells requires signals and receptors5 types of extracellular signals4 classes of receptors

Hypotheses about root problem in Graves’ diseaseThyroid overstimulated (too much TSH or works ‘too well’)

External signals ‘normal’ but response in thyroid notappropriate

Testing the hypothesesIF 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/receptorinteraction

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 terminiPolarity of proteins

Levels of Protein Structure

Adapted from: http://www.bmb.psu.edu/courses/bisci004a/chem/profold.jpg Benjamin Cummings. Ltd. 2001

Primary Structure

Secondary Structure

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?

TSH Receptor: from “The Thyroid Manager” Ch16

Plasma membrane

Extracellular

Cytosolic

Can we predict protein structure?

Motifs and Domains

How do you change a protein’s shape?

Alter the chainChange 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-Receptorinteraction ‘too strong’

According to this hypothesis and what wenow 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 elevatedTSH levels are decreasedTSH/TSH receptor interactions have same

binding constant vs. normal.

Therefore: Perfectly logical hypothesis…….

Now what?

Not supported by data

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?