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Chapter 4. The Three-Dimensional Structure of Proteins Part 2. Chapter 4, Part 2: Learning Goals. Know the structures and functions of collagens, role of ascorbic acid (vitamin C) in collagen structure. Know globular protein structure and families.

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Chapter 4

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Chapter 4

The Three-Dimensional

Structure of Proteins

Part 2


Chapter 4, Part 2: Learning Goals

  • Know the structures and functions of collagens, role of ascorbic acid (vitamin C) in collagen structure.

  • Know globular protein structure and families.

  • Know how de-naturation and re-naturation works or sometimes doesn’t.


Collagen Triple Helix

Left Handed, 3 aa/turn


Prolyl-4-hyroxylase Hydroxylates Protein as Procollagen

Hyrdoxproline is necessary to keep some prolines in the “exo” form to allow the collagen triple helix to form.


Prolyl-4-hydroxylase is a Di-oxygenase can Catalyze Two Reactions

Without Vitamin C, the iron of the first enzyme becomes oxidized and Inactive. Ascorbate actually keeps the enzyme iron reduced although this diagram does not show it.


Hydroxylysine Cross Links Collagen Triple Helix Strands


Iriquois showing Jacques Cartier how to make Cedar Tea - a source of Vitamin C


James Lind’s experiment could not be done today. Why?

Did he lack a control group?

Was there something else?


Newly Discovered Bond in Collagen IV

The Sulfilimine Bond

Between a hydroxylysine and methionine

Vanacore, R, et al. 2009. A sulfilimine bond identified in collagen IV. Science. 325:13230. Sept 4, 2009


Sulfilimine Bond – Evolutionary Conservation


Human Serum Albumin (Mr = 64,500)if it was:

This figure has a flaw. Horizontal dimensions are OK, Verticals are off in two ways: different scale and globular form is way too small.


Structures of Myoglobin


What about “random coil” or “random structure”?

Where is it in myoglobin? - go back to previous slide, it represents 22% of the amino acids in myoglobin!

Is it random? Yes and No!! Both are correct why?

Is it coil? Yes and No!! Both are correct why?


Heme in Myoglobin


Structures of some Small Proteins


A


Troponin has 2 Domains

Each Domain has a Distinct Function: Binding Ca++


Two Small Motifs

Here alpha helix connects Alpha turn alpha are

two beta-structures common on some DNA

binding proteins


Smaller Motifs into Large Motifs


Protein Families – Classes and Folds


All Beta Protein Families


Alpha/Beta Protein Families


Alpha + Beta Protein Families


Max Perutz and John Kendrew


Quaternary Structure of Hemoglobin

2 α and 2 β


Quaternary Structure: Symmetry


Polio Virus and Tobacco Mosaic Virus

A


Protein Stability and Folding

  • A protein’s function depends on its 3D-structure

  • Loss of structural integrity with accompanying loss of activity is called denaturation

  • Proteins can be denatured by:

    • heat or cold

    • pH extremes

    • organic solvents

    • chaotropic agents: urea and guanidinium hydrochloride


Thermal and Chemical Protein Denaturation

Irreversible

Reversible

or Urea


Ribonuclease Refolding Experiment

  • Ribonuclease is a small protein that contains 8 cysteines linked via four disulfide bonds

  • Urea in the presence of 2-mercaptoethanol fully denatures ribonuclease

  • When urea and 2-mercaptoethanol are removed, the protein spontaneously refolds, and the correct disulfide bonds are reformed

  • The sequence alone determines the native conformation

  • Quite “simple” experiment, but so important it earned Chris Anfinsen the 1972 Chemistry Nobel Prize


Reversible Unfolding with Mercaptoethanol

CH3-CH2-SH

This step must be done very slowly


Simulated Folding


Proteins folding follow a distinct path


Creutzfledt-Jakob Disease:Human Spongiform Encephalopathy

Vacuoles Contain a Missfolded Protein – in Brain Tissue


Prions

Infectious proteins

Inherited and transmissible by ingestion, transplant, & surgical instruments

PrPC, normal cellular prion protein, on nerve cell surface

PrPSc, scrapie protein, accumulate in brain cells forming plaques


Prion Miss-folding

PrPSc

PrPc

2

3

4

1

Lysosome

Endosome

5

6

7

8


PrP Folding


Chaperones prevent misfolding


Chaperonins facilitate folding


GroEL and GroES


Protein Folding  Alzheimer’s Disease, Type 2 Diabetes and Parkinson’s Disease

A


Amyloid Fibers Stabilized by F

Different Amyloid diseases depend on organ the fibers occur

A

A


Summary of Forces Driving Protein Structure

1.  hydrophobic interactions contribute strongly to protein folding and stabilization  ultimately burring hydrophobic R groups with at least two layers of secondary structure covering them up to exclude water.  

2.  alpha and beta structures are usually in different layers. Their R-groups generally do not allow mixing.

3.  Secondary structure near each other (in primary sequence) are usually stacked (except in quaternary structure).

4.  beta structure is most stable when slightly twisted. The great example being the beta-barrel (Fig 4-20) of many membrane proteins.

5. Beta bends can not form knots.


Things to Know and Do Before Class

  • Know collagen structure and the role of vitamin C.

  • Structure of globular proteins, circular dichroism, and the main idea of protein families (there are over 800).

  • Denaturation and Renaturation (or not) of proteins

    4. One of the largest unsolved puzzles in modern biochemistry: the details of how proteins fold.

  • Roles of Chaparones.

  • Be able to do EOC Problems 7-11 Problem 12 makes you calculate the molecular weight of the DNP-aa in the diagram.


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