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Protein Folding in the Cell – 1

BIOC 212

Winter 2015

Jason C. Young

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What is Biochemistry?

“Biochemistry is the study of the structure, composition, and chemicalreactions of substances in living systems.”

(American Chemical Society)

“Biochemistry is the study of chemical processes within and relating to

living organisms.

By controlling information flow through biochemical signaling and the

flow of chemical energy through metabolism, biochemical processes

give rise to the complexity of life.

Today, the main focus is in understanding how biological moleculesgive rise to the processes that occur within living cells, which in turn

relates greatly to the study and understanding of whole organisms.”

(Wikipedia)

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Foundational Concepts

• Evolution

• Matter and Energy Transformation

• Homeostasis

• Macromolecular Structure and Function

• Biological Information

• American Society for Biochemistry and Molecular Biology (ASBMB),

National Science Foundation (NSF)

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Biochemistry at McGill

Liberal Major Honours

BIOC 212 Molecular Mechanisms of Cell Function * * *

BIOC 300D1/2 Laboratory in Biochemistry * * *

BIOC 311 Metabolic Biochemistry * * *

BIOC 312 Biochemistry of Macromolecules *

*

*

BIOC 396 Undergraduate Research Project

BIOC 404 Biophysical Chemistry c *

BIOC 450 Protein Structure and Function c * *

BIOC 454 Nucleic Acids c * *

BIOC 458 Membranes and Cellular Signaling c c

BIOC 462 Research Laboratory in Biochemistry

*

BIOC 491 Independent Research c

BIOC 503 Immunochemistry c c

BIOC 570 Biochemistry of Lipoproteins

* Required

c Complementary

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U1 and U2

• BIOC 212 Molecular Mechanisms of Cellular Function

– thermodynamics and energy; biogenesis of organelles and cells;

cancer; development

• BIOC 300D1/2 Laboratory in Biochemistry

• BIOC 311 Metabolic Biochemistry

– energy generation and its regulation; enzyme catalysis;

metabolism of biological compounds

• BIOC 312 Biochemistry of Macromolecules

– gene expression; transcription and translation, and their

regulation; protein modification

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U3

• BIOC 450 Protein Structure and Function

– folding and assembly of proteins; enzyme catalysis mechanisms

• BIOC 454 Nucleic Acids

– DNA organization, replication and repair; RNA processing, andits regulation of translation

• BIOC 404 Biophysical Chemistry

– techniques for analysis of macromolecules

• BIOC 458 Membranes and Cellular Signaling

– signal transduction across membranes; membrane dynamics

and transport; cell morphology

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Research Courses

• Why Research?

– laboratory skills; communication and critical thinking; introduction

to research community

• BIOC 396 Undergraduate Research Project – prerequisites: CGPA of at least 3.0, permission of supervisor

• BIOC 462 Research Laboratory in Biochemistry

– prerequisite: BIOC 300, Honours program; Majors can inquire

• BIOC 491 Independent Research in Biochemistry

– prerequisite: BIOC 462, Honours program

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BIOC 212

Protein Structure and Folding Dr. Young

Membrane Proteins

Intracellular Traffic and Sorting

Thermodynamics, Equilibrium Dr. Duchaine

Organelle Functions and Metabolism

Cell Junctions and Cell Adhesion Dr. Reinhardt

(Dr. Tiedemann)Extracellular Matrix

Cell Communication Dr. Pause

Cell CycleCancer

Model Organisms and Development Dr. Bouchard

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Young Lecture Topics

Protein Folding

1. Introduction to proteins

2. Structure and folding

3. Chaperones

4. Modifications and degradation

Membranes

1. Membrane lipids2. Membrane proteins

3. Targeting to endoplasmic reticulum (ER)

4. Chaperones and degradation in ER

Intracellular Traffic and

Sorting

1. Vesicle formation

2. Vesicle targeting and fusion

3. Lysosome and Nucleus

4. Mitochondria

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Suggested Reading

• Molecular Biology of the Cell, Alberts et al. 4th or 5th edition

– 4th ed. online: http://www.ncbi.nlm.nih.gov/books/NBK21054/

– access by “Search This Book” but not download

– identical to paper version

• Molecular Cell Biology, Lodish et al. 5th edition

http://www.ncbi.nlm.nih.gov/books/NBK21054/

http://www.ncbi.nlm.nih.gov/books/NBK21054/

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The Cell

David Goodsell, Scripps

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Cellular Proteins

• Proteins are the main functional components in cells

• Genes and mRNA are linear

• Proteins are made as linear polypeptides by cytosolic ribosomes,

but fold into 3-dimensional conformations• Folding provides physical stability and functional surfaces

• The sequence of a protein determines its structure, function and

localization

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Amino Acids

• 20 different amino acids

• Side chains have different chemical characteristics:

– hydrophobic, polar or charged (acidic or basic)

– small or large

– covalently linked into polypeptides

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Polypeptides

• Peptide bonds in the backbone are uncharged but polar

• Charge and hydrophobicity of a polypeptide is determined by the

side chains

• Both side chains and backbone can form non-covalent contacts with

other amino acids

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Polypeptide Backbone

• The peptide bond is planar and cannot rotate

• Rotation around the bonds to the central carbon (Cα) is possible

• Therefore, the polypeptide backbone has limited freedom of rotation

• Some rotation angles between amino acids (residues) in a

polypeptide are preferred

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Non-Covalent Bonds

• Interactions between residues of a polypeptide stabilize structure

– hydrophobic interactions (exclusion of water)

– hydrogen bonds

– van der Waals interactions (transient dipoles between all atoms)

– ionic bonds

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Disulfide Bonds

• Secretory proteins often have covalent disulfide bonds between

cysteine side chains

– extracellular proteins, inside secretory organelles

– disulfides reinforce structure

• Cytosolic proteins do not have disulfide bonds – cytosol, nucleus, mitochondria

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Units of Protein Structure

• Primary structure – amino acid sequence

• Secondary structure – local conformation patterns

– stretches of polypeptide can have regular arrangements of the

polypeptide backbone and position of side chains – common structures are α-helices and β-sheets

– loops have no regular secondary structure and can be flexible

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Alpha-Helix

• α-helix:

– backbone is coiled

– hydrogen bonds between each turn of helix backbone

– side chains point outwards

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Beta-Sheets

• β-strands – backbone is extended almost straight

– several strands pack sideways into a β-sheet

– hydrogen bonds between the backbone strands

– side chains on alternate sides

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Tertiary Structure

• Tertiary structure – complete three-dimensional arrangement of the

polypeptide

– secondary structure elements are packed against each other to

form the tertiary structure

– hydrophobic contacts between secondary elements – long-range contacts between residues that are far apart in the

primary sequence

loops

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Quaternary Structure

• Quaternary structure: the assembly of multiple polypeptides

(subunits) into a final protein

– interactions between subunits are very stable

• monomer: single polypeptide with no quaternary structure

• dimer: two polypeptide subunits• trimer, tetramer, 5-mer, 6-mer etc.

• oligomer: many subunits

haemoglobin tetramer

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Protein Folding

• The folded state of proteins depends on hydrophobic interactions in

the interior

– other non-covalent interactions and rigidity constraints contribute

• Polar side chains usually form outer surface

• Native State (completely folded) is the most stable conformation

native state

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Importance for Folding

• hydrogen bonds stabilize secondary structures

• hydrophobic interactions stabilize tertiary and quaternary structures

hydrophobic interactions many, strong

hydrogen bonds many, moderate

Van der Waals interactions many, weak

ionic bonds few, strong

disulfide bonds few, covalent

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Which amino acid side chains can form these interactions?

• can the polypeptide backbone form any of these interactions?

hydrophobic interactions

hydrogen bonds

Van der Waals interactions

ionic bonds

disulfide bonds

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End of 1

• Molecular Biology of the Cell, Alberts et al. 4th or 5th Ed.

– Ch. 3, protein structure, protein function

2015 folding 1 pdf

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