Grad School: Biochem (Quaternary Structure - Gunn Lecture)

Quaternary Structure

the arrangement and interaction of multiple protein subunits (or chains) to form a multi-protein complex

Physiological Advantages of Quaternary Structure

combination of multiple protein domains allows proteins to acquire new functions by creating binding sites, having more than one protein working together can improve efficacy of a reaction (i.e two binding sites) or provide regulation (i.e. shield a binding site), interacting with another protein can also confer added stability and protection from degradation

Homo-Oligomers

made up of repeating subunits of the same protein chain, can range from 2-N subunits (i.e. homodimer)

Example of homo-oligomer

Glutamine Synthetase, Homododecamer

Hetero-oligomers

made up of more than one protein subunit

complexity of naming hetero-oligomers?

the meaning of the name gets more complex as the number of proteins increases. for example a heterotetramer could be A/A/B/B or A/B/B/B or A/B/C/D or any combination of four proteins as long as there are at least two unique ones

What interactions make a stable quaternary structure?

hydrophobic interactions, hydrogen bonds, ionic bonds, disulfide bonds, van der waals

Hydrophobic interactions

burying nonpolar residues to prevent interaction with polar aqueous environments

hydrogen bonds

bonds formed between the oxygen in the carbonyl group in one amino acid interacts with the hydrogen atom in the nitrogen of the amino group from a second amino acid

Aggregation

quaternary structure gone bad, the clustering of multiple items together into a single group (general), clumping of proteins together inside or outside cells

Would you say that a homo-oligomer is an aggregation of a single protein?

technically yes based on the general definition, but the term is not usually used this way

General def of aggregation

the clustering of multiple items together into a single group

Biochemistry Definition of Aggregation

clumping of proteins together inside or outside of cells, mis-folded or intrinsically disordered proteins are more likely to form aggregates

Hemoglobin

two identical a chains and two identical B chains, in sickle cell anemia hemoglobin consists of two identical a chains and two identical mutated B chains. This error causes proteins to aggregate into a fiber (with helical symmetry) and reduce the ability to carry oxygen

Secreted Lipases

break down lipids into free fatty acids

Where do lipoprotein lipase filaments typically arrange in vesicles?

Near the membranes

Amyloids

proteins that form aggregates with a conserved cross-beta structure. These aggregates then group into fibrillar structures.

What gives rise to amyloids?

homo-oligomerization, intrinsically disordered proteins, misfolded or partially folded proteins

Types of Cross-Beta Structure

Parallel in-register, anti-parallel (single and multi-layer), B-solenoid

Why is the cross beta very stable and hard to break apart?

many h-bonds and some hydrophobic interactions play a role, proteasomes can’t pull it apart

Anti-parallel (multi-layer)

B-solenoid

Antiparallel (single)

Parallel in-register

How amyloids affect cells?

amyloid plaques are not digestable, theorized that disrupt the normal function of proteasome and cause ROS generation, can perturb ER membrane, block nucelocytoplasmic transport of protein and RNA, can spread from cell-to-cell

Cyclic Symmetry

symmetry arrangement in a circular pattern around a rotational, useful in creating binding pockets

Dihedral Symmetry

symmetry arrangement that involves multiple symmetry axes

Cubic Symmetry

Complex symmetries, common in viral capsids (icosahedral)

Helical Symmetry

each subunit is related to each other by a fixed pitch and rise, different from alpha helices

What does symmetric assembly help proteins achieve?

helpful for enzymes that bind symmetric ligands (such as palindromic DNA), facilitate allosteric regulation, create hubs of protein activity in the cell to make it more efficient and easier to regulate