07/14/2025 1.01 Protein Structure and Function (FOM OMS1)

Protein folding

The process by which a linear polypeptide chain acquires a specific, biologically active three-dimensional structure.

Amino-acid sequence

The linear order of amino acids in a protein that dictates its final structure and function.

Minimum length for folding

≈70 amino acids are generally required for a polypeptide to stably fold into a defined structure.

Hydrophobic interaction

Non-polar side chains cluster away from water, driving folding and stabilizing a protein’s interior.

Hydrogen bond (in proteins)

An attraction between an electronegative atom (O or N) and hydrogen, helping stabilize secondary and tertiary structures.

Charged side-chain repulsion

Electrostatic repelling forces between like-charged residues (e.g., Glu–Glu or Lys–Lys) that can hinder α-helix formation.

α-Helix constraint: electrostatics

Attraction or repulsion between successive charged residues can promote or destabilize helix formation.

α-Helix constraint: bulkiness

Large adjacent side chains create steric hindrance that destabilizes a helix.

α-Helix constraint: i + 3/i + 4 interactions

Side chains three or four residues apart interact, affecting helix stability.

Proline effect

Proline’s rigid ring and lack of amide hydrogen break or kink α-helices and disrupt folding.

Glycine flexibility

Small, non-chiral glycine allows high backbone mobility, favoring coils or loops rather than rigid helices.

Disulfide bond

Covalent linkage between two cysteine residues that stabilizes tertiary structure.

Primary structure

The linear sequence of amino acids in a polypeptide chain.

Tertiary structure

The overall three-dimensional folding of a single polypeptide, including interactions among secondary structures.

Point mutation

Single nucleotide change in DNA that can substitute one amino acid, potentially altering protein function.

Sickle cell anemia

Disease caused by Glu6→Val mutation in β-globin, leading to abnormal hemoglobin aggregation.

Hemoglobin C

Variant hemoglobin from Glu6→Lys mutation in β-globin, causing mild hemolytic anemia.

Tay-Sachs disease

Neurodegenerative disorder from various point mutations in HEXA, altering a single amino acid in Hexosaminidase A.

Cystic fibrosis

Condition in which deletion of three nucleotides in CFTR removes Phe508, producing misfolded chloride channel protein.

Fibrodysplasia Ossificans Progressiva (FOP)

Bone-forming disorder due to Arg202→His mutation in ACVR1 receptor.

Scurvy

Collagen disorder from vitamin C deficiency that decreases proline hydroxylation, weakening connective tissue.

Huntington disease

Neurodegenerative disease caused by expansion of a polyglutamine (CAG) tract in huntingtin protein.

Gaucher’s disease

Lysosomal disorder; point mutations such as N370S or L444P in β-glucocerebrosidase impair enzyme folding/function.

CFTR (Cystic Fibrosis Transmembrane Conductance Regulator)

Membrane protein whose ΔPhe508 mutation leads to misfolding and cystic fibrosis.

Anemia

A condition characterized by an insufficient number of healthy red blood cells or the presence of abnormal hemoglobin.

Normal Hemoglobin Range

13.5–17.5 g/dL in men, 11.5–16 g/dL in women, and 14–20 g/dL in infants.

Hemoglobinopathy

Any genetic disorder of hemoglobin structure, production, or subunit association that results in anemia.

Structural Hemoglobin Defect

Disease caused by a point mutation that replaces one amino acid in a globin chain, altering hemoglobin function (e.g., HbS, HbC).

Synthesis (Production) Defect

A mutation that lowers synthesis of one globin chain, creating an imbalance and resulting in thalassemia.

Abnormal Subunit Association

Lack of one globin chain forces identical chains to tetramerize, producing non-functional hemoglobin (e.g., α-thalassemia).

Hemoglobin A (HbA)

Normal adult hemoglobin composed of two α and two β chains (α2β2).

Hemoglobin A2 (HbA2)

Minor adult hemoglobin (<3%) consisting of two α and two δ chains (α2δ2).

Hemoglobin F (HbF)

Fetal hemoglobin with two α and two γ chains (α2γ2); predominant before birth.

Hemoglobin S (HbS)

Variant with β-chain mutation Glu6→Val; forms a2βS2 and causes sickle cell disease.

Sickling Electrophoresis Test

At alkaline pH, HbS migrates more slowly toward the anode than HbA because it is less negatively charged—used diagnostically.

Sickle Cell Trait

Heterozygous state (one HbS, one normal β gene) that is usually benign.

Sickle Cell Anemia

Homozygous HbS disease marked by painful crises, hemolytic anemia, hyperbilirubinemia, infection risk, and RBC lifespan <20 days.

Hemoglobin C (HbC)

β-chain mutation Glu6→Lys; produces mild hemolytic anemia and splenomegaly (a2βC2).

Hemoglobin E (HbE)

β-chain mutation Glu26→Lys triggering alternate splicing; causes mild β-thalassemia phenotype common in Southeast Asia.

Hemoglobin Constant Spring

Mutation elongating the α chain; unstable mRNA and protein create a thalassemic phenotype.

Hemoglobin H Disease

α-thalassemia intermedia with deletion of three α genes; tetramer of β chains (β4) leads to microcytic hypochromic hemolytic anemia.

Hemoglobin Bart Syndrome

Severe α-thalassemia (hydrops fetalis) with γ4 tetramers; usually results in stillbirth or early neonatal death.

β-Thalassemia Major

Near-complete absence of β-chain production causing severe anemia and transfusion dependence.

β-Thalassemia Intermedia

Partial reduction of β-chain synthesis producing moderate anemia.

Point Mutation

Single nucleotide substitution in DNA leading to one amino acid change in a protein.

Hyperbilirubinemia

Elevated bilirubin level in blood, commonly seen in chronic hemolytic anemia such as sickle cell disease.

Proteostasis

The dynamic balance between correct protein folding (via chaperones) and removal of misfolded proteins (via the ubiquitin-proteasomal system).

Chaperones

Specialized proteins (e.g., heat-shock proteins) that assist other proteins in achieving or regaining their proper 3-D conformation.

Heat-Shock Proteins (HSP60, HSP70)

Major molecular chaperones induced by stress that guide folding and prevent aggregation of nascent or damaged proteins.

Protein Disulfide Isomerase (PDI)

ER enzyme–chaperone that catalyzes formation/rearrangement of disulfide bonds to aid protein folding.

Metastable Protein

A protein whose native state is only marginally stable and prone to misfolding without chaperone help.

Ubiquitin-Proteasomal System

Cellular machinery that tags misfolded or damaged proteins with ubiquitin and degrades them in the proteasome.

Protein Aggregation

Clumping of misfolded proteins into insoluble deposits, often toxic and linked to age-related diseases.

Reactive Oxygen Species (ROS)

Highly reactive by-products of metabolism that oxidize amino acids and promote protein damage during aging.

Protein Oxidation

Covalent modification of amino acid side chains by ROS, leading to carbonyls, disulfide cross-links, and loss of sulfhydryls.

2-Oxohistidine

An oxidized derivative of histidine formed during aging-related protein oxidation.

Methionine Sulfoxide

Oxidized form of methionine that can disrupt protein structure and function in aged tissues.

Dityrosine Cross-Link

Covalent bond between two tyrosine residues created by oxidative stress, stabilizing harmful protein aggregates.

Carbonylation

Introduction of carbonyl groups into proteins via oxidation, a hallmark of protein aging and degradation signals.

Posttranslational Modification (PTM)

Chemical alteration of proteins after translation (e.g., phosphorylation, deamidation, methylation) that regulates folding and function.

Phosphorylation

Reversible addition of a phosphate group (Ser/Thr/Tyr) by kinases; aging-related dysregulation impairs protein synthesis/folding.

Protein Kinase C (PKC) Pathway

Signaling cascade whose inactivation with age is linked to neurodegeneration such as Alzheimer’s disease.

Deamidation

Spontaneous conversion of Asn/Gln to Asp/Glu, altering charge and destabilizing proteins (e.g., lens crystallins in cataracts).

Methylation (Protein)

Addition of methyl groups to Arg, Lys, His (or acid side chains) that increases surface hydrophobicity, fostering misfolding.

Hydrophobic Interactions

Non-polar side-chain associations driving protein folding; weakened balance contributes to age-related misfolding.

Disulfide Bond

Covalent S-S linkage between cysteines stabilizing protein structure; formation/rearrangement aided by PDI.

Thermodynamic Stability

Energy difference between folded and unfolded states; decreases with oxidative damage in aging proteins.

Proteasomal Decline (Aging)

Age-associated reduction in proteasome activity, lowering degradation of misfolded proteins and fueling aggregation.

Chaperone Decline (Aging)

Reduced expression/function of HSPs with age, impairing folding and refolding capacity.

Proteostasis Imbalance

Combined effect of reduced chaperone/proteasome activity, increased misfolding, and aggregation during aging.

Alzheimer’s Disease (AD)

Neurodegenerative disorder linked to age-related proteostasis failure and accumulation of misfolded amyloid-β and tau.

Parkinson’s Disease (PD)

Movement disorder associated with aggregation of α-synuclein due to impaired proteostasis in aging neurons.

Cataract Formation

Lens clouding accelerated by deamidation and aggregation of crystallin proteins in aging eyes.

Protein Surface Hydrophobicity

Measure of exposed non-polar residues; rises after methylation, promoting aggregation in aged proteins.

Proteins

Biomolecules made of amino acids that perform structural, regulatory, and energetic roles in living organisms.

Amino Acid

Organic molecule containing an amino group, carboxyl group, hydrogen atom, and side chain

Peptide Bond

Covalent bond linking the carboxyl carbon of one amino acid to the amino nitrogen of the next

Primary Structure

Linear, one-dimensional sequence of amino acids in a protein, written from N-terminus to C-terminus; nonfunctional by itself.

N-terminus

The end of a polypeptide chain with a free amino group; starting point for primary sequence notation.

C-terminus

The end of a polypeptide chain with a free carboxyl group; terminal point of the primary sequence.

Secondary Structure

Local 3-D folding of the backbone into α-helices or β-sheets stabilized mainly by hydrogen bonds.

α-Helix

Right-handed spiral secondary structure stabilized by intra-chain hydrogen bonds every fourth residue.

β-Sheet

Secondary structure consisting of aligned β-strands connected by hydrogen bonds; can be parallel or anti-parallel.

Tertiary Structure

Overall 3-D arrangement of a single polypeptide, formed by interactions among secondary structures and solvent.

Quaternary Structure

Assembly of multiple tertiary-structured subunits into a functional multi-subunit complex.

Electrostatic Interaction

Attraction between oppositely charged side chains (ionic bonds) within or between polypeptides.

Hydrogen Bond

Weak interaction between a hydrogen atom covalently bonded to electronegative atom and another electronegative atom; stabilizes secondary and higher structures.

Hydrophobic Interaction

Association of non-polar side chains to avoid water, driving protein folding and stability.

Disulfide Bond

Covalent linkage between sulfur atoms of two cysteine residues, reinforcing tertiary and quaternary structures.

Van der Waals Interaction

Weak, distance-dependent forces between atoms that contribute to protein stability when closely packed.

Ribosome

Cellular organelle where amino acids are polymerized into polypeptides, establishing primary structure.

Actin & Myosin

Contractile proteins enabling muscle movement; examples of proteins with specialized functions.

Enzyme

Protein catalyst that accelerates biochemical reactions without being consumed.

Hormone (Protein-based)

Protein or peptide acting as a chemical messenger to regulate physiological processes.

Antibody

Immunoglobulin protein that recognizes and neutralizes pathogens.

Transport Protein

Protein that carries nutrients or molecules across membranes or within the bloodstream.

Fluid Balance (Protein Role)

Proteins act as buffers to maintain osmotic pressure and regulate body fluid volume.

Protein Energy Yield

Proteins provide approximately 4 calories of energy per gram when metabolized.

Hemoglobin

Quaternary protein (α₂β₂ tetramer) in red blood cells; each subunit binds a heme group for O₂ transport.

Catalase

Tetrameric enzyme containing heme and NADP that detoxifies hydrogen peroxide.