Tertiary Structure

1
Tertiary Structure

• Globular proteins (enzymes, molecular machines)
• Variety of secondary structures
• Approximately spherical shape
• Water soluble
• Function in dynamic roles (e.g. catalysis,
  regulation, transport, immunity)

2
Tertiary Structure

• Fibrous Proteins (fibrils, structural proteins)
• One dominating secondary structure
• Typically narrow, rod-like shape
• Poor water solubility
• Function in structural roles (e.g. cytoskeleton,
  bone, skin)

3
Tertiary Structure

• Membrane Proteins (receptors, channels)
• Inserted into (through) membranes
• Multi-domain- membrane spanning, cytoplasmic,
  and extra-cellular domains
• Poor water solubility
• Function in cell communication (e.g. cell
  signaling)

4
Quaternary Structure

• Definition Organization of multiple chain
  associations
• Oligomerization- Homo (self), Hetero (different)
• Used in organizing single proteins and protein
  machines
• Specific structures result from long-range
  interactions
• Electrostatic (charged) interactions
• Hydrogen bonds (O?H, N? H, S ? H)
• Hydrophobic interactions
• Disulfides only VERY infrequently

5
Quaternary Structure
The classic example- hemoglobin a2-b2
6
Protein Folding

• Folded proteins are only marginally stable!!
• 0.4 kJmol-1 required to unfold (cf.
  20/H-bond)
• Balance of loss of entropy and stabilizing
  forces
• Protein fold is specified by sequence
• Reversible reaction- denature (fold)/renature
• Even single mutations can cause changes
• Recent discovery that amyloid diseases (eg. CJD,
  Alzheimer) are due to unstable protein folding

7
Protein Folding

• The hydrophobic effect is the major driving force
• Hydrophobic side chains cluster/exclude water
• Release of water cages in unfolded state
• Other Forces stabilizing protein structure
• Hydrogen bonds
• Electrostatic interactions
• Chemical cross links- Disulfides, metal ions

8
Protein Folding

• Random folding has too many possibilities
• Backbone restricted but side chains not
• A 100 residue protein would require 1087 s to
  search all conformations (age of universe lt 1018
  s)
• Most proteins fold in less than 10 s!!
• Proteins fold along specific pathways

9
Protein Folding Pathways

• Usual order of folding events
• Secondary structures formed quickly (local)
• Secondary structures aggregate to form motifs
• Hydrophobic collapse to form domains
• Coalescence of domains
• Molecular chaperones assist folding in-vivo
• Complexity of large chains/multi-domains
• Cellular environment is rich in interacting
  molecules? Chaperones sequester proteins and
  allow time to fold

10
Relationships Among Proteins

• I. Homologous very similar sequence (cytochrome
  c)
• Same structure
• Same function
• Modeling structure from homology
• II. Similar function- different sequence
  (dehydrogenases)
• One domain same structure
• One domain different
• III. Similar structure- different function (cf.
  thioredoxin)
• Same 3-D structure
• Not same function

11
Relationships Among Proteins

• Many sequences can give same structure
• Side chain pattern more important than sequence
• When homology is high (gt50), likely to have
  same structure and function (structural genomics)
• Cores conserved
• Surfaces and loops more variable
• 3-D shape more conserved than sequence
• There are a limited number of structural
  frameworks