Tertiary StructureTertiary 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 StructureTertiary 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 StructureTertiary 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 StructureQuaternary 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 StructureQuaternary Structure

The classic example- hemoglobin 2-2

Protein FoldingProtein FoldingFolded 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 FoldingProtein FoldingThe 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 FoldingProtein 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 PathwaysProtein Folding PathwaysUsual 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 ProteinsRelationships Among ProteinsI. 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 ProteinsRelationships 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*