SMART TEAM

Students Modeling A Research Topic: The Journey Explained

What is SMART Team?

Definition: science program

where high school students learn

about a specific protein and

construct a three-dimensional

model of that protein.

Team

Anna Grim

Bryan Lampkin

Dua Her

Rachel Babiarz

The University’s Center for

BioMolecular Modeling is

the center for SMART

Team.

Milwaukee School Of Engineering

Funding: NIH National Center for

Research Resources, Department of

Education for Educational Sciences

and Howard Hughes Medical Institute.

Purpose

Focus: to tell the

“molecular story” of NS1

protein and influenza

infections. In addition,

modeling the NS1 protein.

Modeling Tool: Rasmol

Rasmol

Definition: computer modeling program.

Models are created by using commands to

highlight specific parts of the protein.

Proteins were downloaded from a national data bank.

Part 1

Virus Background Information&

The NS1 Protein

“So What?”

–Learning how viruses/influenzas invade (such as H5N1 and H1N1)

– Understanding how our immune system battles against the flu

– Increased knowledge of NS1 can help avoid future viruses

–Relates to stronger and nastier influenzas (such as swine flu)

Virology

The branch of medicine that

focuses on the study of

viruses

Micro-Anatomy of Virus

-Nucleic acid enclosed in a protein shell.

-Approximately 15-20 nanometers in diameter.

-May have DNA or RNA that is double-stranded or single-stranded .

-Genetic material is covered by a protein coat.

http://www.google.com/images?q=anatomy+of%20a%20virus&um=1&hl=en&client=

How Does a Virus Invade?

1. Virus enters body.

2. Virus’s Antigen binds to cell through hemagglutinin.

3. Virus enters the cell through endocytosis.

4. A clathrin-coated vesicle is formed around the virus.

http://www.invivogen.com/images/RLR_pathway.jpg

How Does a Virus Invade?

6. Virus’ RNA passes through the nucleus and is replicated.-Lysogenic Cycle-Lytic Cycle

7. The replicated viruses leave the cell.

Fact: One virus enters the cell

and results in the replication

of millions of viruses that

leave the cell.

5. Once inside the cell, the vesicle breaks apart.

– NS1 protein (non-

structural protein)

– Found in a virus

– Encoded within an

influenza virus

The NS1 Protein

http://web5.cns.utexas.edu/news/wp-content/uploads/2009/12/NS1A-PNAS_cover4.jpg

Taking a Closer Look

• The NS1 protein is a gene segment located in the inside of a virus

• Influenza A, B, and C viruses contain the NS1 protein

• Viruses with NS1 protein are H5N1 (bird flu) and H1N1 (swine flu)

NS1’s Role

• Binds RNA messengers of host cell from activation

• Attacks TRIM-25 protein – TRIM-25 assists RIG-1

protein– RIG-1 sends out alarm

signals throughout cell

• Slows down pre-mRNA production of a cell

http://focus.hms.harvard.edu/2007/051807/images/RIG-I-TRIM25.gif

A Sign of Hope?– An Antiviral Target against Influenza?

• NS1 binds to the CPSF30 human protein

• CPSF30 protects our cells from infections

• Within the binding site, zinc fingers (F2,F3) from the CPSF30 protein cuts down the virus’s ability to duplicate by blocking the binding between CPSF30 and the NS1 protein

• This binding site can suggest a potential antiviral target against the influenza virus

http://web5.cns.utexas.edu/news/wp-content/uploads/2009/12/NS1A-PNAS_cover4.jpg

Protein Modeling

NS1 Protein Before

NS1 Protein After

NS1 Protein

GuideYellow: Active Site

Green: 7 Beta Sheets

Blue: 3 Alpha Helices

Orange: Hydrogen Bonds

Immunology

The branch of medicine concerned with the

ability of an organism to resist a infection by

the action of antibodies.

Immunity

Innate Immunity: defends the host

from infection by an immediate

nonspecific respond to pathogens.

Adaptive Immunity: antigen-specific

immune response and includes a

"memory" that makes future

responses against a specific antigen.

Acquired Immunity: acquired by the vaccination of the transfer of antibody

.

Innate vs. Adaptive Immunity

Immunology

T-cells: identify, directly attack and

destroy infectious agents.

Interferons: proteins made and

released by lymphocytes in

response to the presence of

pathogens - such as viruses,

bacteria, or parasites.

RIG-1: required for the production

of interferons in response to RNA

viruses.

Immunology

Macrophages: molecules that

engulf antigens and other necrotic

tissue.

Cytokines: signaling molecules that are used in cellular communication.

Tumor Necrosis Factor: cytokine involved in a systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction.

http://www.itb.cnr.it/flex/images/D.0ce220a1911164afd50b/boraschi_1.jpg

Definition: method of determining the

arrangement of atoms within a crystal, in

which a beam of X-ray strikes a crystal

and diffracts into many specific directions.

In 1962 they were awarded the Nobel Prize in Chemistry.

Began in the 1950s when Max Perutz and Sir John Cowdery Kendrew used it to

study the structure of sperm whale myoglobin. http://ysm.research.yale.edu/images/78.4/articles-structures-crystallography.jpg

Crystallography

Part 2

The Interferon (IFN) &

relation with NS1 Protein

Interferon• Detects and fights off infections invading our body

• Classified as a Cytokines– Cytokines are from the immune system– Purpose is to warn the cells of invasions

• Role of Interferon:– Triggers other immunity cells to activate – Builds up other uninfected cells’ resistant towards the new

infections– Forms interferon-stimulated genes (ISGs) to fight off

viruses

Types of Interferons

• Type I IFN (alpha and beta)

–Produces cells resistant against viral infections–Produced from cells in the body

• Type II IFN (gamma)

–Control how the immune system functions–Produced from T lymphocytes and natural killer cells

Connection with NS1

• Interferons decrease the virus’s ability to spread

•Unfortunately, not all viruses are affected by interferons

•Example: H1N1 influenza virus is encoded with a Non-Structural Protein 1 (NS1)

•NS1 resists the presence of interferons…not good

Conclusions• Viruses that contain NS1 protein are harder to get rid of

• Our immune systems are not familiar with new viruses

• Immune systems takes longer to destroy viruses with NS1 protein

• Knowing about NS1 now can aware us of future nastier viruses

• Studies are being done to shut down NS1 protein receptor

Acknowledgements

–Dr. Shannon Colton (SMART team coordinator)

–MSOE - Center of Biomolecular modeling

–SMART team program

–Rasmol program

–Mr. Heeren (assisting DCE SMART team)

Bibliography

• Featured Website: WWW.GOOGLESCHOLAR.COM

•http://www.onmilwaukee.com/images/articles/ho/holidaycarepackage/holidaycarepackage_fullsize_story1.jpg

• http://viromag.files.wordpress.com/2009/02/influenza-virus-diagram.jpg• http://www.invivogen.com/images/RLR_pathway.jpg

•http://science.nationalgeographic.com/staticfiles/NGS/Shared/StaticFiles/Science/Images/Content/flu-virus-e06074-xl.jpg

• http://web5.cns.utexas.edu/news/wp-content/uploads/2009/12/NS1A-PNAS_cover4.jpg• http://focus.hms.harvard.edu/2007/051807/images/RIG-I-TRIM25.gif

• http://ysm.research.yale.edu/images/78.4/articles-structures-crystallography.jpg• http://pathmicro.med.sc.edu/book/immunol-sta.htm

• http://pathmicro.med.sc.edu/ghaffar/innate.htm• http://www.geneontology.org/images/diag-immunology-sm.png

• http://www.ncdnaday.org/immunology.jpg• http://www.cbi.wur.nl/NR/rdonlyres/B299B497-3031-48C6-BFB8-B6DCDCCC93D4/94540/

• http://www.vet.cornell.edu/oge/immunology/pix/Clark1.jpg