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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
Chapter 4

The Three-Dimensional

Structure of Proteins

Part 2


Chapter 4 part 2 learning goals
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
Collagen Triple Helix

Left Handed, 3 aa/turn


Prolyl 4 hyroxylase hydroxylates protein as procollagen
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
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.




James Lind’s experiment could not be done today. Why? source of Vitamin C

Did he lack a control group?

Was there something else?


Newly discovered bond in collagen iv
Newly Discovered Bond in Collagen IV source of Vitamin C

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



Human serum albumin m r 64 500 if it was
Human Serum Albumin (M source of Vitamin Cr = 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
Structures of Myoglobin source of Vitamin C


What about random coil or random structure
What about “random coil” or “random structure”? source of Vitamin C

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
Heme in Myoglobin source of Vitamin C



A source of Vitamin C


Troponin has 2 domains
Troponin has 2 Domains source of Vitamin C

Each Domain has a Distinct Function: Binding Ca++


Two small motifs
Two Small Motifs source of Vitamin C

Here alpha helix connects Alpha turn alpha are

two beta-structures common on some DNA

binding proteins




All beta protein families
All Beta Protein Families source of Vitamin C


Alpha beta protein families
Alpha/Beta Protein Families source of Vitamin C


Alpha beta protein families1
Alpha + Beta Protein Families source of Vitamin C


Max perutz and john kendrew
Max Perutz and John Kendrew source of Vitamin C


Quaternary structure of hemoglobin
Quaternary Structure of Hemoglobin source of Vitamin C

2 α and 2 β


Quaternary structure symmetry
Quaternary Structure: Symmetry source of Vitamin C



Protein stability and folding
Protein Stability and Folding source of Vitamin C

  • 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
Thermal and Chemical Protein Denaturation source of Vitamin C

Irreversible

Reversible

or Urea


Ribonuclease refolding experiment
Ribonuclease Refolding Experiment source of Vitamin C

  • 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
Reversible Unfolding with Mercaptoethanol source of Vitamin C

CH3-CH2-SH

This step must be done very slowly


Simulated folding
Simulated Folding source of Vitamin C



Creutzfledt jakob disease human spongiform encephalopathy
Creutzfledt-Jakob Disease: source of Vitamin CHuman Spongiform Encephalopathy

Vacuoles Contain a Missfolded Protein – in Brain Tissue


Prions
Prions source of Vitamin C

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
Prion Miss-folding source of Vitamin C

PrPSc

PrPc

2

3

4

1

Lysosome

Endosome

5

6

7

8


Prp folding
PrP Folding source of Vitamin C


Chaperones prevent misfolding source of Vitamin C


Chaperonins facilitate folding source of Vitamin C


Groel and groes
GroEL and GroES source of Vitamin C


Protein folding alzheimer s disease type 2 diabetes and parkinson s disease
Protein Folding source of Vitamin C Alzheimer’s Disease, Type 2 Diabetes and Parkinson’s Disease

A


Amyloid fibers stabilized by f
Amyloid Fibers Stabilized by F source of Vitamin C

Different Amyloid diseases depend on organ the fibers occur

A

A


Summary of forces driving protein structure
Summary of Forces Driving Protein Structure source of Vitamin C

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
Things to Know and Do Before Class source of Vitamin C

  • 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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