Center for Structural Biology
Download
Report
Transcript Center for Structural Biology
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)
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)
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)
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 (OH, N H, S H)
Hydrophobic interactions
Disulfides only VERY infrequently
Quaternary Structure
The classic example- hemoglobin a2-b2
Protein Folding
Folded proteins are only marginally stable!!
~0.4 kJ•mol-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
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
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 < 1018 s)
Most proteins fold in less than 10 s!!
*Proteins fold along specific pathways*
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
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
Relationships Among Proteins
Many sequences can give same structure
Side chain pattern more important than
sequence
When homology is high (>50%), 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*