Human biochem lecture 10

Lecture 10 – Proteins: Secondary, Tertiary, and Other Structures

• Date: February 13th, 2025

• Reading Material: Biochemistry: Concepts and Connections, Chapter 6, Pages 146-158

Page 2: Lecture Overview

• Disease of the Day: Prion Disease

  • Overview of infectious proteinopathies

  • How prions cause disease and what diseases exist

  • Tissue appearance and general symptoms

• Secondary and Other Protein Structures

  • Introduction to alpha helices, beta sheets, and other structures

  • Role of amino acids in structure formation

• Ramachandran Plots

  • Examination of secondary structures in fibrous proteins

  • Specific structures: Keratins, Fibroin, Collagen

  • Concluding with globular proteins and tertiary structures

Page 3: Prions – What Are They?

• Definition: Prions - proteinaceous infectious particles

  • Distinct from typical infectious agents (bacteria, viruses)

  • They are solely proteins, lacking nucleic acids

  • Do not replicate; induce misfolding in normal proteins

  • Infection transmission is difficult, cannot be transferred through sneezing

Page 4: Mechanism of Prion Disease

• Normal prion proteins (PrP(C)) exist in cell membranes.

• Misfolding can occur spontaneously or via genetic mutation/infection.

• Accumulation of dysfunctional proteins leads to disease.

  • Unfolded proteins cannot be degraded by proteosomes or lysosomes.

• PrP(Sc) interacts with PrP(C), converting normal proteins into infectious forms, perpetuating the cycle.

Page 5: Human Prion Diseases

• Approximately 9-10 distinct prion diseases in humans, arising from:

  • Spontaneous cases

  • Genetic origins

  • Infectious agents

• Notable diseases include:

  • Kuru

  • Sporadic CJD (sCJD) and familial CJD

  • Fatal familial insomnia (FFI)

  • Iatrogenic CJD

Page 6: Notable Prion Cases

• Kuru: Linked to ritualistic cannibalism; brain consumption spread infection.

• sCJD: The most frequently encountered prion disease.

• FFI: Features insomnia leading to fatal outcomes.

• Iatrogenic CJD: Resulting from infected medical tools.

Page 7: Pathology of Prion Diseases

• Transformation from PrP(C) to PrP(Sc) results in accumulation of beta sheets.

• Formation of fibrils: long non-degradable protein strands.

Page 8: Tissue Pathology

• Vacuoles: Characteristic damage resulting in "spongiform" appearance.

  • Caused by cell death leaving voids in tissue.

Page 9: Signs of Pathology

• Key pathological features include:

  • Spongiform degeneration

  • Presence of PrP plaques

  • Gliosis

  • Florid plaques

Page 10: Behavioral Effects of Prion Diseases

• Cognitive dysfunction is prominent, leading to:

  • Irritability, anger, delusions, and hallucinations.

• Prognosis: patients typically succumb within 1-2 years post-diagnosis.

• Many prion diseases are spontaneous, poorly understood, and untreatable.

Page 11: Introduction to Protein Structures

• Primary Structures: Linear polypeptide chains coded by DNA.

  • Modifications can happen post-translation.

• Secondary Structures: Formed via local hydrogen bonding post-assembly.

  • Common types include alpha helices and beta sheets.

• Tertiary Structures: Final 3D arrangements of polypeptides.

• Quaternary Structures: Complexes of multiple subunits.

Page 12: Examples of Protein Structures

• Primary Structure: Amino acid sequence of human beta globin.

• Secondary Structure: Helical conformations highlighted.

• Tertiary Structure: Describes the stable folded configuration.

• Quaternary Structure: Hemoglobin's assembly of subunits.

Page 13: Fundamental Bond Angles

• Phi (Φ): Bond angle between N and C alpha.

• Psi (Ψ): Bond angle between C alpha and C-O.

Page 14: Common Secondary Structures

1. Alpha helices (right-handed)

2. Beta sheets

3. 310 helices

4. Polyproline II helix

5. Left-handed alpha helices

Page 16: Alpha Helices

• Formed via hydrogen bonds between:

  • Oxygen of carboxyl and nitrogen of amino groups.

• Side chains extend outward, influencing hydrophilicity.

Page 18: Beta Sheets

• Two forms of beta sheets:

  • Anti-parallel: N and C terminals run opposite.

  • Parallel: N and C terminals run in the same direction.

• Bonds formed between nitrogen and oxygen of different residues.

Page 20: Other Secondary Structures

• 310 Helix: Rare, characterized by specific hydrogen bonding patterns.

• Polyproline II Helix: No stabilizing hydrogen bonds between turns.

• Left-handed Alpha Helix: Rare and less stable.

Page 21: Ramachandran Plots

• Indicate allowed bond angles (phi and psi) for amino acids.

• Useful for identifying secondary structure via crystallography.

• Identify non-allowed conformations and steric clashes.

Page 25: Fibrous Proteins Overview

• Types: Proteins that maintain extended structures (fibrous) as opposed to globular.

• Typically serve structural roles rather than complex functions.

Page 26: Types of Fibrous Proteins

• Main fibrous proteins:

  • Keratin: Found in hair/nails.

  • Fibroin: Forms silk in spiders/worms.

  • Collagen: Major component in connective tissues.

Page 27: Keratin Types

1. Alpha (α) Keratin: Found in hair and nails.

2. Beta (β) Keratin: Forms structures like feathers.

Page 32: Collagen Structure and Function

• Composed of a triple helix arrangement of polypeptides.

• Key amino acids: Glycine, Proline, 4-hydroxyproline.

• Forms connective tissues, such as skin and bones.

Page 34: Overview of Globular Proteins

• Vast majority of proteins; involved in:

  • Enzymatic activity, transport, signaling, and detoxification.

Page 36: Classifying Globular Proteins

1. Types of secondary structures present.

2. Number of structural domains.

3. Types of repeating patterns within these domains.

Page 37: Upcoming Topics

• Continue with tertiary structures and globular proteins.

• Introduction to Chapter 7: Protein Functions, including antibodies and muscle proteins.