The Biochemistry and Cell Signaling Pathway of MC1R Published August 2012
Updated September 2013
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LESSON
TEACHER MATERIALS
The Making of the Fittest:
Natural Selection and Adaptation
THE BIOCHEMISTRY AND CELL SIGNALING PATHWAY OF MC1R
OVERVIEW
This lesson serves as an extension to the short film The Making of the Fittest: Natural Selection and Adaptation, which can
be downloaded at http://www.hhmi.org/biointeractive/making-fittest-natural-selection-and-adaptation. Students use
amino acid sequences from the rock pocket mouse genome to illustrate the different levels of protein structure and the
relationship between a protein’s structure and function. In addition, students analyze the MC1R signaling pathway in
both light- and dark-colored rock pocket mouse populations. Through their analyses, students come to understand the
concepts of cell signaling. Finally, students hypothesize how the change in sequence and thus protein function might
directly affect the coat-color cell signaling pathway of the rock pocket mouse populations.
KEY CONCEPTS AND LEARNING OBJECTIVES
• Proteins fold into three-dimensional structures of varying levels of complexity.
• A protein’s function is dependent on its three-dimensional structure, which is determined by the sequence of amino acids
in the protein.
• Cell signaling pathways mediate the sensing and processing of stimuli. They involve signal reception, transduction, and
cellular response.
• In melanocytes, the MC1R signaling pathway is involved in determining a rock pocket mouse’s coat color.
Students will be able to
• use an amino acid class chart to determine whether an amino acid in a protein sequence is nonpolar, polar, acidic, or basic;
• analyze amino acid data to hypothesize how changes in the sequence of the MC1R protein domains might affect the
function of the protein; and
• analyze amino acid data to hypothesize how the change in sequence and thus protein function might affect the coat color
of rock pocket mouse populations.
CURRICULUM CONNECTIONS
Curriculum
Standards
NGSS (April 2013)
HS-LS1-1, HS-LS3-1
HS.LS1.A, HS.LS4.B, HS.LS4.C
Common Core (2010)
CCSS.ELA-Literacy.RST.9-10.3, CCSS.ELA-Literacy.RST.9-10.4,
CCSS.ELA-Literacy.RST.9-10.7
AP Biology (2012–13)
3.D.1, 3.D.3, 4.A.1, 4.B.1
IB Biology (2009)
2.4, 3.5, 4.1, 4.3, 7.3, 7.4, 7.5, C.1, G.1
KEY TERMS
adaptation, evolution, mutation, natural selection, trait, variation
TIME REQUIREMENTS
This lesson was designed to be completed within one 50-minute class period; additional time for the analysis questions
might be required depending on students’ pace.
SUGGESTED AUDIENCE
This lesson is appropriate for high school biology (AP, IB) and introductory college biology.
The Biochemistry and Cell Signaling Pathway of MC1R
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LESSON
TEACHER MATERIALS
The Making of the Fittest:
Natural Selection and Adaptation
PRIOR KNOWLEDGE
Students should understand the relationship between protein structure and function and should be comfortable with
the processes of transcription and translation. Students should also be familiar with the basics of cell signaling, including
the function of ligands, reception, transduction pathways, second messengers, and response.
MATERIALS
amino acid class chart
blue, red, green, and yellow colored pencils
TEACHING TIPS
• Although this lesson can be completed as a stand-alone lesson, we recommend that students first complete the related
lesson “Molecular Genetics of Color Mutations in Rock Pocket Mice,” which can be downloaded at
http://www.hhmi.org/biointeractive/molecular-genetics-color-mutations-rock-pocket-mice.
• Students can complete the procedure individually or in small groups. Analysis questions are designed to be challenging
and should be completed by groups of three or four students to encourage discussion and help identify misconceptions.
• Students use color to classify amino acid types in Step 3 of the procedure. If you do not have access to a color printer, you
should compare student work to the answer key (on page 3 of this lesson) on your computer screen.
The Biochemistry and Cell Signaling Pathway of MC1R
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LESSON
TEACHER MATERIALS
The Making of the Fittest:
Natural Selection and Adaptation
QUESTIONS
1. Where is the melanocortin 1 receptor located, and what is its role in the cell?
The melanocortin 1 receptor is embedded in the cell membranes of specialized cells called melanocytes. It plays a
role in the determination of coat color.
2. a. What does the following shape on the gene tables represent?
The shape represents a phospholipid molecule, which is found in all cell membranes. Phospholipids make up
the phospholipid bilayer structure of membranes.
b. Why is the phospholipid membrane included in the figure with respect to the receptor’s location and three-dimensional
structure? (Hint: Refer to the introduction and Question 1 above.)
The receptor is located within the membrane. The MC1R protein is a transmembrane protein with
extracellular domains, transmembrane domains, and intracellular domains. Inclusion of the phospholipid
shapes on the gene tables helps visualize the portion of the protein extending out of the cell (extracellular)
and the portion extending into the cytoplasm (intracellular).
3. Using the information provided in the introduction, create a simple flowchart depicting the MC1R pathway. There should be
a minimum of five steps in the pathway. Be sure to include reception, a portion of the transduction pathway, and the cellular
response.
Sample flowchart:
4. Complete the table below comparing the chemistry of amino acids in the wild-type MC1R protein and the mutant MC1R
protein.
Comparison Table
Amino Acid Mutation Position
Number
Wild-Type MC1R
Amino Acid Chemistry
Mutated MC1R
Amino Acid Chemistry
Example 1
Polar (hydrophilic), neutrally
charged
Electrically charged, negative
(acidic)
018
Electrically charged, positive
(basic)
Polar (hydrophilic), neutrally
charged
109
Electrically charged, positive
(basic)
Nonpolar (hydrophobic),
neutrally charged
160
Electrically charged, positive
(basic)
Nonpolar (hydrophobic),
neutrally charged
233
Polar (hydrophilic), neutrally
charged
Electrically charged, positive
(basic)
MC1R Receptor
(G protein–
coupled)
α-MSH
Hormone
G Protein
cAMP
(secondary
messenger)
Eumelanin
Production
The Biochemistry and Cell Signaling Pathway of MC1R
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LESSON
TEACHER MATERIALS
The Making of the Fittest:
Natural Selection and Adaptation
5. The wild-type (normal) Mc1r gene results in the light coat-color phenotype, while the mutated Mc1r gene results in the dark
coat-color phenotype. Based on your knowledge of the MC1R signaling pathway (Question 3), cell signaling, and the chemistry
of the amino acid changes (Question 4), write a hypothesis for each of the following questions.
a. How could the two extracellular mutations lead to the dark phenotype? (Hint: Think about the chemistry of the amino
acids, particularly their charge.)
The extracellular mutations at positions 018 and 109 both change a positively charged arginine amino acid to
a neutrally charged amino acid (polar cysteine and nonpolar tryptophan, respectively). This change in
electrical charge in the extracellular domains of the receptor protein could increase the affinity of the ligand
for the receptor, therefore amplifying the pathway signal and thus producing more eumelanin. The change in
charge could also decrease the effect of an antagonist from another gene, which would also lead to the
production of more eumelanin and a dark coat color.
b. How could the two intracellular mutations lead to the dark phenotype? (Hint: Think about the chemistry of the amino
acids, particularly their charge.)
The missense mutation found at position 160 changes a positively charged arginine to a neutral, nonpolar
tryptophan, and the mutation at position 233 replaces glutamine, which is neutral and polar, with a positively
charged and basic histidine. These changes will ultimately change the shape of the intracellular domains of
the protein, perhaps producing an overly active receptor, which would lead to the production of eumelanin.
In addition, this change could increase the activation of the G protein without the need of a ligand. This
increase in activation would amplify the levels of cAMP, thus increasing eumelanin production.
c. How does the wild-type Mc1r gene result in the light phenotype? (Hint: It might be helpful to think of it as not resulting in
the dark phenotype.)
The normal receptor conformation requires a ligand for activation of the G protein. If the ligand is not readily
available, the production of eumelanin will decrease, resulting in a light coat color. Another hypothesis might
be the presence of an antagonist from another gene in the rock pocket mouse that, when expressed,
interferes with the MC1R pathway, thus reducing eumelanin production.
Although we do not expect students to know this, a second gene is known to be involved in the coat color
pathway, namely the agouti gene. This gene produces a protein antagonist to the MC1R pathway. The
presence of this antagonist decreases the production of eumelanin and increases the production of
pheomelanin. Obviously, the mice with light-colored coats contain the normal MC1R receptor and related
pathway, and they also contain the agouti gene. During the hair development cycle, there is a pulse of agouti
expression, producing the antagonist that results in the deposition of pheomelanin in the hair. This results in
the light coat-color phenotype. Preliminary results indicate that the mice with the dark Mc1r alleles have
hyperactive MC1R receptors that increase the levels of cAMP, thus producing eumelanin in the melanocytes
and resulting in the dark phenotype, even though these mice also contain the agouti gene and the protein
antagonist it produces.
AUTHOR
Ann Brokaw, Rocky River High School, Ohio
FIELD TESTERS
Beth Dixon, Western Sierra Collegiate Academy; David Knuffke, Deer Park High School; Chris Monsour, Tiffin Columbian High School
