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 Adapted from: Benjamin Cummings. Ltd. 2001http:// Primary Structure Secondary Structure

Levels of Protein Structure Tertiary Structure:

Quaternary structure Protein Kinase C Interacting Protein.

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 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…….

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?