1

Ooopsies & Schedule❖ I posted Periodic Table w/ ‘normal’ deadline

instead of intended of 9-12 @ 10 p.m.

❖ Kudos to all of you who did it by the posted deadline!!

❖ But for the sake of fairness, deadline now 9-16

❖ Next round: Read paper this weekend

❖ Assessor on Monday/due Thurs p.m.

2Quiz custodiet ipsos Quiz custodiet ipsos

custodes?custodes?

3Who builds the builder?

❖ Machines are 3D ‘folded’* strings of amino acids: ‘proteins’

❖ What forms (folds) the machines out of strings?

❖ Does anybody see a problem with such a solution?

*Folding is the correct term for an amino acid string being brought into correct 3D shape

4

What do to with my What do to with my string of blobs?string of blobs?

5

Beads on a string❖ It is plausible that a string of distinct, shaped

‘feels’ would self-assemble: Prof. Nowicki’s example

❖ Potential example of amino acid ‘beads’ on a protein ‘string’ shown

http://sun.menloschool.org/~dspence/biology/chapter3/chapt3_13.html

6

Say hello to a special friend

❖ Next week in lab, you’ll revel in the glory of histidine

❖ Today’s special pal: cysteine (recall from Easter Egg Hunt)

❖ Concept: the 20 amino acids are a collections of generalist pieces & specialists with unique capabilities!

7Sulfur + Sulfur = SulfurSulfur

oxidize

8On the importance of bonding ‘H’

9On the importance of bonding ‘H’

(+)

(-)

10

alpha helix

11Details, details

12One, two, three, four

Steps in assembling a Big Machine

13

Great experimentsGreat experimentsBoiling an egg, writ small: Boiling an egg, writ small:

Scrambled ribonucleaseScrambled ribonuclease

14The argument

❖ It is plausible that a string of distinct, shaped ‘feels’ would self-assemble

❖ alpha-helices, beta-sheets can be drawn; pairings postulated

❖ That’s different from evidence

http://sun.menloschool.org/~dspence/biology/chapter3/chapt3_13.html

How beads organize a string:

15What it is, is...

http://upload.wikimedia.org/wikipedia/commons/c/c0/Ribonuclease_A_7rsa.png

16

Ribonuclease the right way

❖ In a protein chain (a.k.a. polypeptide), nearby sulfur sidechains may be covalently joined

http://guweb2.gonzaga.edu/faculty/cronk/biochem/images/disulfide_bond_formation.gif

Cartoon of previous

17What they then knew

❖ ‘it cuts up RNA’ *

❖ we can tell if RNA intact vs. cut up

❖ (heat drives proteins wild)

❖ (so do some chemicals--like urea. From the name, guess where we can find that?)

*nomenclature moment: ‘enzyme’ = hastenerprotein that does this: -ase

18

Like & unlike an egg

Biochemstry, 5th ed.Berg, Tymoczko &

Stryer

❖ Break disulfide (Cys-Cys through their sulfurs)

❖ ‘Denature’ (unfold)

❖ Cool fast

❖ freezes current state

❖ allow disulfides to reform

❖ It ‘locks in’ to inactive states

19

Like & unlike an egg

Biochemstry, 5th ed. Berg, Tymoczko & Stryer

❖ Disconnect the disulfides

❖ Allow to re-discover its ‘comfy’ shape (re-fold on its own)

❖ Allow disulfides to re-lock

❖ Function!

20

Finding yourself… protein style

21

What’s going on in What’s going on in there?there?

Techniques for seeing that which cannot be Techniques for seeing that which cannot be seenseen

22

From the lab❖ By detection of different smells, you deduced

❖ The presence of molecules

❖ Their flightiness

❖ Their structural distinctness

❖ Your possession of receptors & pathways

23An important idea

❖ To understand a paper, you don’t necessarily need to understand every component

❖ If I tell you that…

❖ amount of habooxiebooble directly reflects the number of hydrophobic residues in a protein

❖ Protein A has a greater habooxiebooble than Protein B

❖ What can you tell me?

24How can we know the

shape of a protein?❖ X-ray crystallography: the ultimate in (frozen)

truth

❖ Circular dichroism (rotation of polarized light)

❖ All you need to know: it happens, and it happens different for different shapes [conformations] of same 1˚ sequence

❖ Cysteine locking

❖ Tyrosine wiggling

25

Prions: protein Prions: protein folding diseasesfolding diseases

Giving a protein a choice isn’t always a good Giving a protein a choice isn’t always a good ideaidea

26

What is life?

❖ Replicates

❖ Instructs

27Mystery diagnosis

❖ Diseases with LOOOONG onset times--years or decade+

❖ Infectious particles resistant to UV treatments that blow DNA, RNA out of the water

Kuru is an incurable degenerative neurological disorder (brain disease) that is a type of transmissible spongiform encephalopathy, caused by a prion found in humans.[1] The term "kuru" derives from the Fore word "kuria/guria", 'to shake'.[2], a reference to the body tremors that are a classic symptom of the disease; it is also known among the Fore as the laughing sickness due to the pathologic bursts of laughter people would display when afflicted with the disease. It is now widely accepted that Kuru was transmitted among members of the Fore tribe of Papua New Guinea via cannibalism.[3]

http://en.wikipedia.org/wiki/Kuru_(disease)

28What’s a ‘prion’?

❖ Alas ‘ protein infectious particle’

❖ !?! How can this be?

❖ I will later argue that genetic material must be ‘base like’ with rigid presentation of binary information

❖ Proteins do not qualify! How can they direct reproduction?

❖ We may talk viruses & such much later, but this is specifically a protein folding issue, so it’s here

29Deadly alternatives

The secret: conversion of pre-existing material to the dark side; not de novo creation

Still, this very much blurs the distinction about which structures can & cannot instruct

Biologic Science, Scott Freeman, Fig. 3.15

Shown is a small section of a much larger protein--but this is the source of the trouble

30But wait! There’s more...

❖ Note that besides the bonds between the two, each offers donors & acceptors to the outside

❖ Imagine this going on and on and on...

❖ One ‘prionized’ protein converts another, and they convert others...

31

Prion diseases: FYI

❖ http://www.cdc.gov/ncidod/dvrd/prions/

32Homework

❖ Assessor drops on Mon.

❖ I challenge you to read on your own 1st

❖ Vocal linked from homepage

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