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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

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Previously in Cell Bio

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Previously in cell bio l.jpg

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

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


Now what l.jpg

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

Now what?


What do we know so far l.jpg

What do we know so far?

  • Thyroid is ‘overacting’

  • Pituitary normally responsible for thyroid

  • stimulation through levels of TSH

  • Graves’ patients have normal/decreased levels

  • of TSH in blood

  • Binding affinity between TSH and TSH-R normal


More of what we know l.jpg

  • TSH is water soluble hormone (why is this important?)

More of what we know

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”


Even more l.jpg

  • Thyroid plasma membrane is barrier

  • to polar molecules

Even more

  • TSH interacts with a receptor on

  • the surface of thyroid cells

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?


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Characteristics of Transmembrane Proteins

  • Hydrophobic face of protein in transmembrane region

    • -one continuous structure or multiple regions of 2° structure

  • Charges ‘anchor’ transmembrane region

  • Asymmetric orientation


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Peripheral Membrane proteins

Characteristics

  • Associations with membrane not as strong

  • Various means of attachment

  • -Protein-protein

  • -Protein-phospholipid head

Fig 3-32 Molecular Cell Biology by Lodish et al.


Membranes and membrane proteins l.jpg

Membranes and membrane proteins

How can a polar signal gain access to the cytosol

  • Direct access: From the ‘outside’

    • Pores

    • Channels

    • Pumps

    • From cytosol to cytosol

    • Gap junctions


Membrane proteins l.jpg

Membrane proteins

Indirect access: Receptors

If signaling molecule never

gains access to cytosol how can

the information be transmitted?

Extracellular domain

Plasma Membrane

Cytoplasmic Domain

TSH Receptor:from “The Thyroid Manager” Ch16


Transmembrane receptors l.jpg

Transmembrane receptors

  • Same general structure as other transmembrane proteins

  • Able to bind specific ligand

  • Ligand binding causes conformational change

What change in the TSH receptor could cause

overproduction of T3 and T4

How could you test your hypothesis?


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Allosteric transitions

What are they, why are they important,

How do they relate to signal transduction

  • R T state transitions

  • Cooperative binding

Examples DNA helicase and ras (links from index page)


Other mechanisms that regulate protein function l.jpg

Other mechanisms that regulate protein function

  • Compartmentalization

  • Change in rate of synthesis

Common traits?

  • Cleavage

  • Phosphorylation/dephosphorylation

Common traits?


Receptor s role summary l.jpg

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?


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2nd Messengers and Signaling Cascades

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’)


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