Previously on Bio308Graves’ Disease data

activating and negative feedback loops are ‘fine’ Therefore: Hypothesis 1 not supported

Not an extracellular signaling problem

Move to Hypothesis 2: Cell Interpreting Signal IncorrectlyBackground on Receptor Activation*What does it takes to be in a membrane

and to be a receptor

Other mechanisms that regulate protein function

•Compartmentalization•Change in rate of synthesis

Common traits?

•Cleavage•Phosphorylation/dephosphorylation

Common traits?

Receptor’s role (summary)Able to transduce signal because of:

•Placement in membrane (span it)•Ability to bind ligand•Ligand -induced conformational changes

So the signal ‘gets in’ without physically crossing membrane

BUT How do you go from a shape change to causing a change in gene expression?

Surface toNucleus:Types of signaling proteins

MBoC4 Fig15-16

Thyroid

What is constitutive activity?

Cascade examples

(not trimeric) G protein switch

Note the dramatic shape change depending upon thebinding partner(s)

cAMP 2nd messenger

Other 2nd messengers

cAMP dep. Protein Kinase

After activation

Transcriptional activation

Others

Your summaries go here

On to Off

Hyper activity is the problem in Graves’ disease-- What ‘should’ happen to each component of the

cascade to make the cascade turn off?

BUT Internal signaling in Graves’ Patients is fine…

There goes another perfectly good hypothesis, rejected due to data.

Next on Bio 308 (class cancelled on Thurs. Use time to catch up)

Graves’ disease: Comparing information from other situationsand disease specific information to come up withanother hypothesis for the molecular basis of this disease

CausesHow does it all add up?

TreatmentsIntroduction to paper discussion: