Levels of Protein Structure & Their Characteristics

Why is the shape of a protein important?

Provides function to a protein

• Proteins are EVERYWHERE in the human body, ranging from transport proteins to enzymes - no shape is one-size-fits-all!

Provides specific solubility to a protein

Denaturation

Protein losing its shape, and therefore entire function/activity and solubility capabilities

Disruption of weak interactions that would normally stabilize the structure

Causes denatured proteins to clump together, causing more harm than simply losing their function

Examples of diseases involving denatured/misfolded proteins

• Sickle cell anemia

• Huntington’s disease

• Parkinson’s disease

• Alzheimer’s disease

• Osteogenesis Imperfecta

• Prion diseases: Mad cow disease, Creutzfeldt-Jakob disease, Kuru disease

Primary Structure

Unique amino acid sequence linked by peptide bonds, forming a polypeptide

Unfolded but has blueprints for how it will fold in the future

Peptide Bond Characteristics

Partial double-bond character between terminal ends of each amino acid (NH+ group and COO- group)

Written N- to C- terminal (L-R)

UNCHARGED

Cis side chain

Relative to a peptide bond between two amino acids, the R side chain is on the same side on one amino acid as the other amino acid’s R side chain

More likely to have steric hindrance (slowing of chemical rxn)

Trans side chain

Relative to a peptide bond between two amino acids, the R side chain is on the same side on one amino acid as the other amino acid’s R side chain

Less likely to have steric hindrance (slowing of chemical rxn)

Torsion angle

Measure of rotation for phi and psi bonds between peptide bonds

Preferred angle is depicted by a Ramachandran plot

• Most favored angles = dark green regions

• Least favored angles = light green regions

• Most conformations are unfavorable due to steric exclusions!

Steric exclusion

Phenomenon where a molecule is too large to fit next to another molecule

Phi bonds Φ

N-C(alpha) bonds

Psi bonds Ψ

C(alpha)-C bond

Secondary Structure

Localized, small 3D structure

Stabilized by H bonding of peptide backbone

• Alpha helixes

• Beta pleated sheets

• Loops

• Turns

Alpha helix

Stabilized by H bonding

• 3.6 amino acids per turn

• Unlikely to have steric exclusions (V, T, I)

• Unlikely to have H bond donors (S, D, N)

• Unlikely to have phi rotation for P due to lack of NH group

Beta pleated sheet

2 or more adjacent polypeptide strands called “B-strands”

Stabilized by H bonding between C=O and N-H groups

Can be parallel or antiparallel

Adopts a twisted shape, but is still beta pleated sheets

Loops and Turns

Changing of direction of polypeptides, usually on the edge or surface of a protein

Stabilized by H bonding

Tertiary Structure

Single completely folded 3D protein structure - may end structure here if fully functional

Stabilized by interactions between R groups and interaction of amino acids far apart in primary structure

Disulfide bonds are created

Functional units:

• Motifs

• Domains

Disulfide bonds

Formed by the OXIDATION of 2 CYSTEINE amino acids, causing covalent cross-linking of polypeptides

VERY strong

Stabilizes tertiary AND quaternary structure

Motifs

Special characteristics of the structure of the protein itself

Combination of multiple secondary structures

Domains

Sections of proteins with a specific function

A single polypeptide may have 1+ domains depending on its final function

Common domains:

• RNA/DNA binding

• Catalytic activity

• Transcriptional activation

• Protein-protein interaction

• Cytoskeleton interaction

Typically represented in colored BOXES

Quaternary Structure

More than 1 polypeptide interacting

Each polypeptide chain is called a SUBUNIT

Stabilized by interaction of side chains

NOT ALL PROTEINS HAVE THIS LEVEL OF ORGANIZATION

Subunit

Single polypeptide in a protein with quaternary structure

Dimer

2 subunits

Homodimer

Heterodimer

Homodimer

2 identical peptide subunits

Heterodimer

2 different peptide subunits

May be encoded by different genes, but nonetheless comes together to make 1 protein subunit

“Complex” quaternary structure

MANY subunits stabilized together to make 1 LARGE protein

3 CLASSES OF PROTEINS

Fibrous proteins

Globular proteins

Membrane proteins

Fibrous proteins

Relatively simple and LINEAR in shape

Functions to provide structural support

• Keratin

• Collagen

• Cytoskeleton proteins (intermediate filaments)

• Muscle proteins (myosin & tropomyosin)

Collagen

Fibrous protein

Component of skin, bone, tendons, cartilage, teeth, etc.

3 intertwined helical polypeptide chains, forming a superhelical cable

• GLY - GLY - PRO sequence is commonly repeated throughout its structure

• Stabilized by steric repulsion of the PRO rings

• Chains interact by H bonding

Defects in collagen structure:

• Osteogenesis imperfecta

• Scurvy

Globular proteins

Compact and roughly spherical in shape

Water SOLUBLE

Functions to provide enzymatic activity and signaling capabilities

• Myoglobin

• Hemoglobin

Membrane proteins

Proteins associated with cellular membranes

• Channels for chemical transport across the membrane

• Carrier proteins for chemical transport across the membrane

Have to interact with hydrophobic AND hydrophilic membrane sections

Water INSOLUBLE

• Exterior of protein = mostly hydrophobic amino acid chains

• Interior of protein = mostly hydrophilic amino acid chains

• Like the phospholipid membrane!