Graves

1
Graves Disease Case Previously
Normal thyroid function requires circuit of
extracellular signaling hypothalamus,
pituitary, thyroid? feedback to beginning
Signaling between any cells requires signals and
receptors 5 types of extracellular
signaling What they are and how they work 8
classes of cell surface receptors (based on
signaling) 4 classes based on generalized
function (S/T kinase, Y kinase, ion channel,
GCPR
Hypotheses for problem in Graves
2
Hypothesis Thyroid being over-stimulated
Normal stimulation results from
TSH/receptor interaction How does the thyroid
know to react? How does a receptor provide
specificity
Hypothesis Mutation in signaling within cell
leading 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?
3
Testing the hypotheses
IF hypothesis is true then what is
expected? What data would suggest the hypothesis
needs to be revised?
4
Graves hypothesis 1 TSH, TSH-Receptor
interaction too strong.. Something to do with
binding specificity
A ligand binds two different receptors . Kd
10-7M for Receptor 1. Kd 10-9M for Receptor
2. For which receptor does the ligand show the
greater affinity? (from textbook)
5
Binding Assays determining Kd for RL complex
with strong affinity
6
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?
7
Side chains
Conventions for writing and speaking about
proteins The N and C termini Polarity of
proteins
8
Levels of Protein Structure
2
3
4
1
ALL other folding depends upon 1 structure
Why can we say this? What are the consequences
of this being true (for any protein in general or
in our case looking at the TSH-receptor case