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='''<font color = 'black'> Tangible Models of Cdc42 Interacting With Intersectin </font>'''=
=='''<font color = 'red'>A Lincoln HS SMART Team Telling a Molecular Story</font><font color = 'black'></font>'''==
[[Image:Lincoln Team 2008.JPG|left|360px]]
 


=='''<font color = 'red'>A Lincoln HS SMART Team Telling a Molecular Story</font><font color = 'black'></font>'''==
<font color = 'red'><b>Abraham Lincoln High School, San Francisco, California</b></font>
:<b>Students</b> -- Cyndi He, Glen Huynh, Aissa Isana, Bradley Jann, Bradford Li, Yaqiao Li, Calvin Ng, Tiffany Saw, Elizaveta Sergeeva, Jacqueline Tam, Allison Trinh, Michelle Xie, Ellen Zhang
:<b>Teacher</b> -- Julie Reis


Abraham Lincoln High School, San Francisco, California
:Students -- Cyndi He, Glen Huynh, Aissa Isana, Bradley Jann, Bradford Li, Yaqiao Li, Calvin Ng, Tiffany Saw, Elizaveta Sergeeva, Jacqueline Tam, Allison Trinh, Michelle Xie, Ellen Zhang
:Teacher -- Julie Reis


Mentors:
<font color = 'blue'><b>Mentors:</b></font>
:UCSF Science and Health Education Partnership -- Sabine Jeske
:<b>UCSF Science and Health Education Partnership</b> -- Sabine Jeske
:UCSF/UCB Joint Graduate Group in Bioengineering -- Angela Chau
:<b>UCSF/UCB Joint Graduate Group in Bioengineering</b> -- Angela Chau
:Institute for Neurodegenerative Diseases, UCSF -- Kurt Giles
:<b>Institute for Neurodegenerative Diseases, UCSF</b> -- Kurt Giles
:Center for BioMolecular Modeling, Milwaukee School of Engineering -- Shannondoah Colton
:<b>Center for BioMolecular Modeling, Milwaukee School of Engineering</b> -- Shannondoah Colton




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='''<font color = 'black'>Abstract for Our Project</font>'''=
='''<font color = 'black'>Abstract for Our Project</font>'''=


==<font color = 'blue'>Abstract</font>==
==<font color = 'blue'>Abstract</font>==
[[Image:Poster picture.jpg|right|380px]]


:Information transfer within the cell relies upon signaling pathways made up of interacting proteins. Rho-family [[GTPase]]s are GTP-binding proteins, which function as molecular switches initially in the "off" state. Interactions with activators turn these GTPases "on" and they then interact with other proteins, leading to a variety of cellular behaviors such as directed movement and changes in cell shape.
:Information transfer within the cell relies upon signaling pathways made up of interacting proteins. Rho-family [[GTPase]]s are GTP-binding proteins, which function as molecular switches initially in the "off" state. Interactions with activators turn these GTPases "on" and they then interact with other proteins, leading to a variety of cellular behaviors such as directed movement and changes in cell shape.


:Traditional methods for visualizing protein structures and interactions are often limited in the amount of information that can be conveyed in two dimensions. Using the rapid prototyping technology at the Milwaukee School of Engineering's Center for BioMolecular Modeling, we have built tangible 3D models of the Rho GTPase Cdc42 in complex with one of its activators. Our model shows the interaction of Cdc42 with the catalytic domains of intersectin, based upon the published crystal structure solved by Snyder, et al (PDB 1KI1, Nature Structural Biology 2002; 9(6): 468- 475). Along with computer visualization tools, tangible 3D models allow students and scientists alike to more fully explore the intricacies of protein interactions.
:Traditional methods for visualizing protein structures and interactions are often limited in the amount of information that can be conveyed in two dimensions. Using the rapid prototyping technology at the Milwaukee School of Engineering's Center for BioMolecular Modeling, we have built tangible 3D models of the Rho GTPase [http://en.wikipedia.org/wiki/CDC42 Cdc42] in complex with one of its activators. Our model shows the interaction of Cdc42 with the catalytic domains of intersectin, based upon the published crystal structure solved by Snyder, et al (PDB 1KI1, Nature Structural Biology 2002; 9(6): 468- 475). Along with computer visualization tools, tangible 3D models allow students and scientists alike to more fully explore the intricacies of protein interactions.


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==<font color = 'blue'>Cell Signaling and Cell Movement</font>==
==<font color = 'blue'>Cell Signaling and Cell Movement</font>==
[[Image:Filopodia.jpg|left|250px]]
[[Image:Filopodia.jpg|left|250px]]


:[[Cell signaling]] is how cells transmit information from the outside environment to inside the cell as well as how cells propagate messages within the cell. Transmembrane receptors at the cell surface detect environmental changes and pass the information on to intracellular signaling proteins. Proteins that make up signaling pathways pass along messages by interacting with each other.
:[[Cell signaling]] is how cells transmit information from the outside environment to inside the cell as well as how cells propagate messages within the cell. Transmembrane receptors at the cell surface detect environmental changes and pass the information on to intracellular signaling proteins. Proteins that make up signaling pathways pass along messages by interacting with each other.
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==<font color = 'blue'>Why build a model?</font>==
==<font color = 'blue'>Why build a model?</font>==
[[Image:Actual 3d models.JPG|right|150px]]


:A 3-dimensional model generated by the polymer printing technology at the Center for BioMolecular Modeling greatly enhances our ability to visualize and explore Cdc42 and its interaction with Intersectin. The complex structures and shapes of these molecules can be appreciated more fully through seeing and touching a physical model. A tangible model can not only aid us in summarizing what we know but can also inspire us and other scientists to ask new questions and come up with new hypotheses about these molecules.
:A 3-dimensional model generated by the polymer printing technology at the Center for BioMolecular Modeling greatly enhances our ability to visualize and explore Cdc42 and its interaction with Intersectin. The complex structures and shapes of these molecules can be appreciated more fully through seeing and touching a physical model. A tangible model can not only aid us in summarizing what we know but can also inspire us and other scientists to ask new questions and come up with new hypotheses about these molecules.


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='''<font color = 'black'>Cdc42: The GTPase</font>'''=
='''<font color = 'black'>Cdc42: The GTPase</font>'''=
[[Image:GDP to GTP.jpg|right|250px]]
[[Image:GDP to GTP.jpg|right|250px]]


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:<scene name='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'>Cdc42/Intersectin Complex.</scene> The orientation of Alanine 59 is the highlight of Cdc42 activation by Intersectin. Alanine 59 causes the displacement of the Mg++ ion which in turn releases GDP from Cdc42’s binding pocket. Cdc42 is then able to accept a new nucleotide, specifically GTP, to become activated.
:<scene name='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'>Cdc42/Intersectin Complex.</scene> The orientation of Alanine 59 is the highlight of Cdc42 activation by Intersectin. Alanine 59 causes the displacement of the Mg++ ion which in turn releases GDP from Cdc42’s binding pocket. Cdc42 is then able to accept a new nucleotide, specifically GTP, to become activated.


<applet load='2rh1.pdb' size='350' frame='true'  align='left' scene='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'/>
<applet load='2rh1.pdb' size='350' frame='true'  align='right' scene='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'/>


1) <scene name='SMART_Lincoln_2009/Cdc42_and_gdp/1'>Cdc42</scene> (yellow) is off when GDP is in its binding pocket. Mg++ is shown in magenta, Alanine 59 in green, Switch 1 in light gold, and Switch 2 in dark orange. Brown depicts the residues interacting with GDP (Lys16 and Cys18).


2) <scene name='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'>Intersectin</scene>(blue) binds to Cdc42, and its DH domain interacts with the GTPase.
1) <scene name='SMART_Lincoln_2009/Cdc42_and_gdp/1'>Cdc42</scene> (<font color = '#FFFF00'><b> yellow </b></font>) is off when GDP is in its binding pocket. <font color = '#FF1493'><b> Mg++ </b></font>is shown in magenta, <font color = '#00FF00'><b> Alanine 59 </b></font> in green, <font color = '#FFA500'><b>Switch 1</b></font> in light gold, and <font color = '#FF6600'><b>Switch 2</b></font> in dark orange. Brown depicts the residues interacting with <font color = '#00BFFF'><b>GDP</b></font> (<font color = '#8B4513'><b>Lys16 and Cys18</b></font>).


3) Thee interaction causes conformational changes in Switch 1 and Switch 2 of Cdc42. _r35 hydrogen bonds to a residue (Glu1244) of the DH domain of Intersectin. Most important is the noticeable change in the orientation of residue 59 (Ala59). Its sidechain flips into the magnesium-binding pocket, causing the release of the Mg++ ion and in turn the release of GDP from Cdc42.


4) Mg++ and GDP fall off from Cdc42. the nucleotide-binding pocket of Cdc42 is now empty.
2) <scene name='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'>Intersectin</scene>(blue) binds to <font color = '#FFFF00'><b>Cdc42</b></font>, and its <font color = '#6A5ACD'><b>DH domain</b></font> interacts with the GTPase.


5) Because the intracellular ratio of GTP to GDP is high, a GTP molecule (dark green) will float into the binding pocket of Cdc42 and activate it.


3) Thee interaction causes conformational changes in <font color = '#FFA500'><b>Switch 1</b></font> and <font color = '#FF6600'><b>Switch 2</b></font> of Cdc42. <font color = '#FF0000'><b>Thr35</b></font> hydrogen bonds to a residue (<font color = '#802AAB'><b>Glu1244</b></font>) of the <font color = '#6A5ACD'><b>DH domain</b></font> of Intersectin. Most important is the noticeable change in the orientation of residue 59 (<font color = '#00FF00'><b>Ala59</b></font>). Its sidechain flips into the magnesium-binding pocket, causing the release of the <font color = '#FF1493'><b> Mg++ </b></font> ion and in turn the release of <font color = '#00BFFF'><b>GDP</b></font> from <font color = '#FFFF00'><b>Cdc42</b></font>.




4) <font color = '#FF1493'><b> Mg++ </b></font> and <font color = '#00BFFF'><b>GDP</b></font> fall off from <font color = '#FFFF00'><b> Cdc42</b></font>. The nucleotide-binding pocket of <font color = '#FFFF00'><b>Cdc42</b></font> is now empty.




5) Because the intracellular ratio of <font color = '#2F6E46'><b>GTP</b></font> to <font color = '#00BFFF'><b>GDP</b></font> is high, a <font color = '#2F6E46'><b>GTP</b></font> molecule (dark green) will float into the binding pocket of <font color = '#FFFF00'><b>Cdc42</b></font> and activate it.








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==''<font color = 'black'>Animation: How Intersectin Activates Cdc42</font>''==






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