Protein Structure & Evolution (Ch. 4)

Protein 3˚ structure (The Fold)

The manner in which secondary structure elements are connected and packed in space.

Protein domain

An independently folding unit usually 40-300 amino acids in length with several alpha helices and/or beta strands.

Protein motif

A smaller region of sequence (as small as 3 amino acids) that is not necessarily an independent folding unit.

EGFR (Epidermal Growth Factor Receptor)

A cancer-associated protein containing a transmembrane domain, tyrosine kinase domain, and specific surfaces for signal binding.

Lock-and-key binding mechanism

Interaction where exact positioning of multiple hydrogen bonds, charges, and hydrophobic surfaces ensures specificity and strength.

Loops in protein structure

Exposed and flexible regions connecting secondary structure elements that tolerate insertions and deletions (indels).

Hydrophobic effect in protein folding

Drives hydrophobic side chains (such as F, W, Y, L) inward to form an interior core, while polar side chains face outward.

Primary (1˚) protein structure

The linear sequence of amino acids determined by the mRNA and gene sequence.

Secondary (2˚) protein structure

Local shape and organization of the polypeptide backbone, dominated by alpha helices, beta sheets, and connecting loops.

Tertiary (3˚) protein structure

The overall 3-dimensional shape and fold of a fully folded polypeptide chain.

Quaternary (4˚) protein structure

The way multiple polypeptide chains assemble and act as subunits in a larger functional complex.

Metabolic and energetic pathways

Cellular pathways responsible for the synthesis, breakdown, storage, and release of small compounds, proteins, DNA, and RNA.

Signaling pathways

Pathways that transmit information into, through, and out of the cell to control growth, patterning, and differentiation.

Mechanical and structural pathways

Pathways including the cytoskeleton and extracellular matrix that control the shape and mechanical properties of cells.

Domain shuffling

An evolutionary process where existing domains are combined to form new genes, avoiding the need to invent proteins from scratch.

Tectorin-alpha

A major component of the tectorial membrane in the inner ear whose mutation causes hearing loss; formed via domain shuffling.

Homology

Similarity between two items because they are descended from a common ancestor (cannot be partial or expressed as a percentage).

Evolutionary convergence

When natural selection independently arrives at similar features or traits in unrelated species (alternative to homology).

AlphaFold2 pair representations

Method where every pair of amino acid residues is represented separately to encode co-evolutionary relationships based on MSAs.

The Central Dogma

The flow of genetic information: DNA is transcribed into RNA, which is translated by ribosomes into proteins.

SARS-CoV-2 Spike S-acylation

The attachment of long-chain fatty acids to cytosolic cysteine residues in the C-terminal cytoplasmic tail of the spike protein.

Hydrophobic amino acids (V, L, I, M)

Valine, leucine, isoleucine, and methionine; frequently substituted for one another during evolution.

Hydrogen bonding distribution in folded proteins

Averages 1.1 H-bonds per residue: 65% between peptide groups, 23% between peptide groups and side chains, and 12% between side chains.

Alpha helix backbone H-bonding

Formed by hydrogen bonds between the carbonyl oxygen (C=O) of one amino acid and the amide hydrogen (N-H) four residues away.

Alpha helix structure & appearance

A rigid, tube-like structure where side chains project outward to interact with other molecules.

Beta sheet structure

Sheets that position side chains alternately above and below the strand; strands can run parallel or antiparallel.

Proline's role in protein folding

Acts as a 'helix breaker' or kink-inducer, helping the backbone form tight turns and loops.

Cysteine and disulfide bonds

Forms covalent disulfide bonds in extracellular proteins; remains reduced and unbonded in the reducing environment of the cytosol.

Plasma membrane compartmentalization

Surrounds the cell and internally segregates regions to maintain distinct chemical conditions inside versus outside.

Amphipathic membrane lipids

Molecules possessing both hydrophilic polar heads and hydrophobic nonpolar tails, driving spontaneous lipid bilayer formation.

Membrane lipid asymmetry

The uneven distribution of specific lipid species between the inner and outer leaflets, such as phosphatidylserine enrichment in the inner leaflet.

Membrane permeability rules

Small nonpolar molecules (like O2) pass freely, whereas ions are nearly impermeable and require specialized channels or transporters.

Transmembrane alpha helix motif

The primary structural motif for membrane-spanning proteins, typically requiring a hydrophobic stretch of about 24 amino acids.

Hydropathy plot peaks

Graph regions highlighting stretches of hydrophobic amino acids that indicate likely membrane-spanning helices.

Piezo mechanosensitive ion channel

A trimeric integral membrane protein with numerous transmembrane helices that senses mechanical membrane tension and transduces it into electrical activity.

Glycoproteins and cell surface glycosylation

Proteins modified with complex oligosaccharides that form a protective, hydrophilic sugar coating on the extracellular cell surface.

Non-ionic vs. ionic detergents

Non-ionic detergents solubilize membranes while preserving protein structure, whereas ionic detergents dissolve membranes and denature proteins.

Coronavirus Spike protein glycosylation

A dense sugar coating on viral spike proteins that masks underlying amino acid epitopes from host antibody recognition.

Alanine (Ala, A)

Features a simple methyl group side chain; hydrophobic, nonpolar, and promotes alpha-helix formation.

Phenylalanine (Phe, F)

Features a hydrophobic benzyl side chain; important for interior core packing and protein stability.

Tyrosine (Tyr, Y)

Features a polar phenolic hydroxyl group; serves as a key phosphorylation target in signaling pathways.

Lysine (Lys, K)

Features a positively charged amino-terminated side chain; involved in ionic bonding and protein interactions.

Threonine (Thr, T)

Features a polar hydroxyl-bearing side chain; frequently acts as a phosphorylation site for kinases.