Week 5: Protein Structure, Folding, and Misfolding in Human Disease

A comprehensive vocabulary review of protein structure levels, thermodynamic folding principles, denaturation, and associated misfolding neurodegenerative disorders based on lecture notes.

$$\alpha\text{-Carbon (C}_\alpha\text{)}$$

The central carbon atom of an amino acid bonded to four distinct groups—an amino group, a carboxyl group, a hydrogen atom, and a variable R side chain—in 19 of the 20 standard amino acids.

Zwitterion

A dipolar ionic form of an amino acid predominant in solutions at neutral pH, in which the amino group is protonated ($-\text{NH}_3^+$) and the carboxyl group is deprotonated ($-\text{COO}^-$).

Primary Structure

The linear sequence of amino acid residues joined together by covalent peptide bonds to form a polypeptide chain.

Secondary Structure

Regular, recurring conformations assumed by local regions of a polypeptide chain, principally comprising $\alpha$-helices, $\beta$-sheets, loops, and turns.

$$\alpha\text{-Helix}$$

The simplest arrangement a polypeptide chain can assume, first characterized by Pauling and Corey, consisting of a coiled, helical backbone stabilized by intramembranous hydrogen bonds.

$$\beta\text{-Sheet}$$

A secondary structural arrangement in which the polypeptide backbone adopts an extended zigzag conformation resembling pleats, held together by inter-strand hydrogen bonds in parallel or antiparallel orientations.

Hydrophobic Effect

The thermodynamic tendency of nonpolar amino acid side chains to cluster within the interior core of a protein to minimize water contact, serving as the main driving force for three-dimensional folding.

Tertiary Structure

The complete three-dimensional conformation of a single polypeptide chain, stabilized by long-range interactions such as hydrophobic forces, hydrogen bonding, ionic salt bridges, and covalent disulfide cross-links.

Quaternary Structure

The multi-subunit assembly formed when two or more folded polypeptide chains (identical homomers or differing heteromers) assemble into a functional complex, exemplified by tetrameric hemoglobin.

Anfinsen's Principle

The concept proven by Christian Anfinsen in 1973 using ribonuclease A showing that the primary amino acid sequence contains all necessary instructions to determine a protein's native three-dimensional tertiary structure.

Molecular Chaperones

Specialized auxiliary proteins that assist nascent or unfolded polypeptide chains to fold properly and prevent nonproductive aggregation in cells where folding does not occur spontaneously.

Melting Temperature ($T_m$)

The denaturation temperature at which equilibrium is reached such that exactly $50\%$ of the protein molecules are folded and the remaining $50\%$ are unfolded.

Ubiquitin-Proteasome System

The primary cellular protein degradation pathway that recognizes misfolded proteins transported out of the endoplasmic reticulum (ER) and proteolytically degrades them into short peptides.

Amyloid Precursor Protein (APP)

A membrane protein encoded on chromosome 21 whose sequential cleavage via the amyloidogenic pathway by $\beta$-secretase and $\gamma$-secretase releases neurotoxic amyloid-$\beta$ ($\text{A}\beta$) peptides.

Presenilins (PSEN1 and PSEN2)

The catalytic subunits of the $\gamma$-secretase enzyme complex whose dominant mutations shift APP processing toward the less soluble and more aggregation-prone $\text{A}\beta 42$ isoform.

Lewy Bodies

Pathological intracellular inclusions found in nerve cells of patients with Parkinson's disease, Lewy body dementia, and related disorders, predominantly composed of aggregated $\alpha$-synuclein and ubiquitin.

$$\alpha\text{-Synuclein}$$

A 140-amino acid natively unfolded neuronal protein that functions in neurotransmitter release control and self-associates into oligomers, protofibrils, and insoluble fibril aggregates in Parkinson's disease.

Huntingtin (HTT)

The protein whose gene contains an unstable trinucleotide CAG repeat expansion, resulting in pathogenic elongated polyglutamine (polyQ) tracts that trigger protein misfolding and neuron degeneration.

CAG Repeat Classification (in Huntington's Disease)

The diagnostic stratification based on triplet counts in the HTT gene: $<28$ repeats is normal, $28\text{--}35$ is intermediate, $36\text{--}40$ shows reduced penetrance, and $>40$ exhibits full clinical penetrance.

Penetrance

The statistical proportion of individuals carrying a particular genetic variant or genotype who actively express the associated clinical phenotype.

Prion Protein (PrP)

An infectious protein that undergoes conformational conversion into insoluble, aggregated forms to cause transmissible spongiform encephalopathies, including scrapie, kuru, Creutzfeldt-Jakob disease, and bovine spongiform encephalopathy.