Graves’ Disease Case: Previously Normal thyroid signaling requires circuit of signaling: hypothalamus, pituitary, thyroid Signaling between any cells requires signals and receptors 5 types of extracellular signaling What they are and how they work 4 classes of receptors (only showed list) Receptors: What are they (describing all of them) Now: More details on the 4 classes of receptors Hypothesizing what goes wrong in Graves’

Types Types of Receptors What types of signals are there and how could the cell react/respond to them? G-protein linked receptors (G protein coupled receptors/GPCR) Ion Channel receptors Enzyme linked receptors (Receptor S/T kinases, Receptor Y kinases Receptor guanylyl cyclases, Protein Y phosphatases, Y-kinase associated receptors H-kinase associated receptors) Intracellular receptors

What is ‘Normal’ Signaling Response Extracellular signal produced….then what

What’s different in a Grave’s disease patient? (hyperthyroidism=increased thyroid function) Patients have increased T3 and T4 in bloodstream YOUR HYPOTHESES? What might make a thyroid put in overtime?

Hypothesis : Thyroid being over-stimulated Hypothesis: Mutation in signaling within cell leading increase in thyroid hormone production Normal stimulation results from TSH/receptor interaction How does the thyroid know to react? How does a receptor provide specificity Normal activation is the result of signal transduction second messenger cascade How does signal transduction work? What could have gone wrong?

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

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

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