Previously in Cell Bio. Signals are detected via binding interactions Binding interactions governed by protein folding Protein folding dictated by amino acid sequence (molecular models as link from index page) Hypotheses for ‘problem’ in Graves’ Disease
Signals are detected via binding interactions
Binding interactions governed by protein folding
Protein folding dictated by amino acid sequence
(molecular models as link from index page)
Hypotheses for ‘problem’ in Graves’ Disease
Positive signals (TRH or TSH) altered to increase amount or affinity for their receptor
Hypothesis one not supported–
TSH correct structure,
Levels of TSH appropriate for levels of T3 & T4 in system (decreased)
TSH/TSHreceptor affinity normal
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?
Notsupported by data
Figure 4-1. Schematic drawing of human TSH, based on a molecular homology model built on the template of a hCG model14. The a-subunit is shown as checkered, and the b-subunit as a solid line. The two hairpin loops in each subunit are marked L1, L3; each subunit has also a long loop (L2), which extends from the opposite site of the central cystine knot. The functionally important a-subunit domains are boxed. Important domains of the b-subunit are marked directly within the line drawing (crossed line, beaded line and dashed line): For further details the reader is referred to Grossman et al.2. (Reproduced from Grossman,M, Weintraub BD, SzkudlinskiMW-Endocrin Rev (4) 18:476-501,1997, with permission of the Endocrine Society).
From “The Thyroid manager”
HOW and WHY is the thyroid responding as though over-stimulated?And to get to the answer of that question: How do signals get passed across membranes?
Fig 3-32 Molecular Cell Biology by Lodish et al.
How can a polar signal gain access to the cytosol
Indirect access: Receptors
If signaling molecule never
gains access to cytosol how can
the information be transmitted?
TSH Receptor:from “The Thyroid Manager” Ch16
What change in the TSH receptor could cause
overproduction of T3 and T4
How could you test your hypothesis?
What are they, why are they important,
How do they relate to signal transduction
Examples DNA helicase and ras (links from index page)
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?
Getting the signal to where it needs to go
For Tuesday: summarize a cascade involving.
1) cGMP2) RTK (growth factor 3) IP3 (inositol triphosphate)
4) Ca++ 5) RTK (insulin) 6) DAG (diacyl glycerol)
Email me one paragraph summary of how it works by
midnight Monday (think ‘handout’)