Transcript sickle cell anemia explained by protein shape, northeast 2012

Framework:
This unit would be taught early in an Introductory Biology course as part of a
broader discussion about biological macromolecules. Students would have
already been introduced to major themes in biology, such as the chemistry of
life (including atomic structure and types of chemical bonds). They will have
just been introduced to the four major types of macromolecules: their building
blocks, chemical properties, and important functional groups. The goals of
this teaching unit will be to reinforce how small chemical changes in proteins
can have a significant impact on the overall structure and function of a
protein, using aggregation of hemoglobin in sickle cell patients as an
example.
The tidbit incorporates the following approaches to active learning:
Think/Pair/Share, clicker questions, brainstorming, and a group worksheet
that is filled out during the activity. The topic is amenable to a discussion
about aspects of diversity pertaining to a disease often associated with a
particular ethnic population. The tidbit contains multiple opportunities for
both formative and summative assessment, for example the instructor could
evaluate how well students understand the chemical properties of amino acid
side chains from the worksheet exercise.
Summer Institute 2012
Harvard
Group 1:
The Interface of Biology and Chemistry
Carol Bascom-Slack
Carlton Cooper
Michal Hallside
Jacqui Johnson
Gillian Phillips
Eugenia Ribeiro-Hurley
Erica Selva
Course Details
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Introductory Biology 1
Week 3 of class
Discussion of Macromolecules of Life
Expected Background
•
Overview of Biology
•
Atomic structure
•
Basic Chemistry of Bonding
•
Types of Macromolecules
•
Hierarchy of peptide structure
Teachable Unit:
Macromolecules of Life
Goal:
• Appreciate the chemical diversity of
macromolecules
• Understand the relationship between the structure
of macromolecules and their function
Objectives
Students should be able to:
• Describe the structure of each of the four
macromolecules of life
• Identify the roles of the macromolecules in a cell
• Describe how the structure of each macromolecule
relates to its function
Teachable Tidbit:
Sickle Cell Anemia Explained by Protein
Shape
Learning Goals
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Understand how hydrophobic and hydrophilic interactions affect
protein structure
Appreciate the importance of correct protein composition for
proper structure
Appreciate the importance of correct protein structure for proper
function
Learning Objectives
Students should be able to:
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Determine if the side chain of an amino acid is mainly hydrophilic
or hydrophobic in nature
Describe how changes in the amino acid sequence of hemoglobin
can lead to aggregation
Sickle Cell Anemia
Symptoms:
Pain in extremities and bones
Fatigue
Pale skin
Dizziness
Headaches
Jaundice
Examination of Red Blood Cells
Sickle Cell Anemia
Normal
Hemoglobin
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A principal protein component of red blood cells
Tetramer composed of two a-subunits and two b-subunits
a-subunits have 141 amino acids while the b-subunits have 146 amino
acids
Each subunit carries oxygen
Brainstorm:
What might cause a difference in
the net charge of these proteins?
Think pair share
Circle: two amino acids containing the most hydrophobic R-groups
Underline: two amino acids containing the most hydrophilic R-groups
Think pair share:
Valine (Val, V)
Glutamate (Glu, E)
Serine (Ser, S)
Leucine (Leu, L)
Lysine (Lys, K)
Threonine (Thr, T)
Hydrophobic amino acid R-group (side chain)
Hydrophilic amino acid R-group (side chain)
Think pair share
Valine (Val, V)
Glutamate (Glu, E)
Serine (Ser, S)
Leucine (Leu, L)
Lysine (Lys, K)
Threonine (Thr, T)
Hydrophobic amino acid R-group (side chain)
Hydrophilic amino acid R-group (side chain)
Think pair share
Valine (Val, V)
Glutamate (Glu, E)
Serine (Ser, S)
Leucine (Leu, L)
Lysine (Lys, K)
Threonine (Thr, T)
Hydrophobic amino acid R-group (side chain)
Hydrophilic amino acid R-group (side chain)
Each blue dot=one
amino acid
α=141 amino acids
β=146 amino acids
β
α
α
β
Approximately what percentage of the 574 amino acids in hemoglobin
do you think you would need to change to cause sickle cell anemia?
Each blue dot=one
amino acid
α=141 amino acids
β
α
α
β
Β=146 amino acids
Where in this folded protein might this
change have occurred?
A. Near the oxygen binding site
B. At the interface between subunits
C. On the surface
D. A and C
E. A, B and C
These are the locations of
the changed amino acids.
Glutamate
(hydrophilic)
Valine
(hydrophobic )
Think-pair-share
Can you come up with an explanation that would link
the aggregation of hemoglobin to the amino acid
change?
Remember: An external hydrophilic amino
acid is replaced with a hydrophobic one
Glutamate
(hydrophilic)
Valine
(hydrophobic)
Teachable Tidbit:
Sickle Cell Anemia Explained by Protein
Shape
Learning Goals
•
•
Understand how hydrophobic and hydrophilic interactions affect
protein folding
Appreciate the importance of the correct protein folding for proper
function
Learning Objectives
Students should be able to:
•
•
Determine if the side chain of an amino acid is mainly hydrophilic
or hydrophobic in nature
Describe how changes in the amino acid sequence of hemoglobin
can lead to aggregation
Extra Information
For a more chemistry centric class the table below may help explain the non-polar (hydrophobic) vs.
polar (hydrophilic) nature of the amino acids. There are multiple hydropathy indexes that can be used
to describe the order of amino acids.
Amino Acid
3-Letter[95]
1-Letter[95]
Alanine
Arginine
Asparagine
Aspartic acid
Cysteine
Glutamic acid
Glutamine
Glycine
Ala
Arg
Asn
Asp
Cys
Glu
Gln
Gly
A
R
N
D
C
E
Q
G
Side-chain
polarity[95]
nonpolar
polar
polar
polar
polar
polar
polar
nonpolar
Histidine
His
H
polar
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Proline
Serine
Threonine
Tryptophan
Tyrosine
Valine
Ile
Leu
Lys
Met
Phe
Pro
Ser
Thr
Trp
Tyr
Val
I
L
K
M
F
P
S
T
W
Y
V
nonpolar
nonpolar
polar
nonpolar
nonpolar
nonpolar
polar
polar
nonpolar
polar
nonpolar
Side-chain charge
(pH 7.4)[95]
neutral
positive
neutral
negative
neutral
negative
neutral
neutral
positive(10%)
neutral(90%)
neutral
neutral
positive
neutral
neutral
neutral
neutral
neutral
neutral
neutral
neutral
Hydropathy
index[96]
1.8
−4.5
−3.5
−3.5
2.5
−3.5
−3.5
−0.4
−3.2
4.5
3.8
−3.9
1.9
2.8
−1.6
−0.8
−0.7
−0.9
−1.3
4.2