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Tertiary Structure

Tertiary Structure. Globular proteins (enzymes, molecular machines) Variety of secondary structures Approximately spherical shape Water soluble Function in dynamic roles (e.g. catalysis, regulation, transport, immunity). Tertiary Structure.

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Tertiary Structure

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  1. Tertiary Structure • Globular proteins (enzymes, molecular machines) • Variety of secondary structures • Approximately spherical shape • Water soluble • Function in dynamic roles (e.g. catalysis, regulation, transport, immunity)

  2. Tertiary Structure • Fibrous Proteins (fibrils, structural proteins) • One dominating secondary structure • Typically narrow, rod-like shape • Poor water solubility • Function in structural roles (e.g. cytoskeleton, bone, skin)

  3. Tertiary Structure • Membrane Proteins (receptors, channels) • Inserted into (through) membranes • Multi-domain- membrane spanning, cytoplasmic, and extra-cellular domains • Poor water solubility • Function in cell communication (e.g. cell signaling)

  4. Quaternary Structure • Definition: Organization of multiple chain associations • Oligomerization- Homo (self), Hetero (different) • Used in organizing single proteins and protein machines • Specific structures result from long-range interactions • Electrostatic (charged) interactions • Hydrogen bonds (OH, N H, S  H) • Hydrophobic interactions • Disulfides only VERY infrequently

  5. Quaternary Structure The classic example- hemoglobin a2-b2

  6. Protein Folding • Folded proteins are only marginally stable!! • ~0.4 kJ•mol-1 required to unfold (cf. ~20/H-bond) • Balance of loss of entropy and stabilizing forces • Protein fold is specified by sequence • Reversible reaction- denature (fold)/renature • Even single mutations can cause changes • Recent discovery that amyloid diseases (eg. CJD, Alzheimer) are due to unstable protein folding

  7. Protein Folding • The hydrophobic effect is the major driving force • Hydrophobic side chains cluster/exclude water • Release of water cages in unfolded state • Other Forces stabilizing protein structure • Hydrogen bonds • Electrostatic interactions • Chemical cross links- Disulfides, metal ions

  8. Protein Folding • Random folding has too many possibilities • Backbone restricted but side chains not • A 100 residue protein would require 1087 s to search all conformations (age of universe < 1018 s) • Most proteins fold in less than 10 s!! • *Proteins fold along specific pathways*

  9. Protein Folding Pathways • Usual order of folding events • Secondary structures formed quickly (local) • Secondary structures aggregate to form motifs • Hydrophobic collapse to form domains • Coalescence of domains • Molecular chaperones assist folding in-vivo • Complexity of large chains/multi-domains • Cellular environment is rich in interacting molecules Chaperones sequester proteins and allow time to fold

  10. Relationships Among Proteins • I. Homologous: very similar sequence (cytochrome c) • Same structure • Same function • Modeling structure from homology • II. Similar function- different sequence (dehydrogenases) • One domain same structure • One domain different • III. Similar structure- different function (cf. thioredoxin) • Same 3-D structure • Not same function

  11. Relationships Among Proteins • Many sequences can give same structure • Side chain pattern more important than sequence • When homology is high (>50%), likely to have same structure and function (structural genomics) • Cores conserved • Surfaces and loops more variable • *3-D shape more conserved than sequence* • *There are a limited number of structural frameworks*

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