Cy
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Cindy Wright
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Ryan Flores
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Pearl Martinez
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Overview |
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Overview
GTPases are key proteins in many critical biological processes. They encompass a large group of enzymes that bind GTP (guanine triphosphate) and undergo a conformational change as GTP is hydrolyzed to GDP (guanine diphosphate) in the presence of a Mg2+ ion. The GTPases can be thought of as molecular clocks for the timing and specificity of events that take place withithe cell
There are five general groups of GTPases:
1. Heterotrimeric G-proteins (invloved in hormonal and sensory signals)
2. Initiation & Elongation Factors (involved in ribosomal protein synthesis)
3. SRP/SR Family (translocate peptides into the ER)
4. Tubulins and Cytoskeletal Motor GTPases
5. Monomeric GTPases: Ras superfamily (signal transduction cascades and motility)
The Ras Superfamily
The Ras superfamily is comprised of more than 50 proteins, each belonging to certain sub-families. Each protein acts as an "on/off" switch for the regulation of different signal transduction cascades and motlities.
The figure above gives details on the functions of each sub-family and the biological process that is regulated.
When GDP is attached to the GTPase, the enzyme is inactivated. The GEF (guanine nuecleotide exchange factor) upstream from the site promotes the release of the GDP so GTP can replace and activate the GTPase. The GTPase remains active until the GTP is hydrolyzed to GDP, this is catalyzed by the GAP (GTPase Activating Protein).
The Ras p21 protein is the founding father of the growing superfamily of GTPases. Ras is located in every cell and is a component in the cell-signanling system that transmits growth signals. When the Ras protein is mutated, it could become an oncogenic form, this occurs when the active GTP form of the protein is not converted into the inactive GDP form as fast as it should, so the growth signal is transmitted for too long. This a brief explanation of uncontrolled cellular growth (cancer/tumors) attached to the GTPase activity.
This presentation will focus on the monomeric Ras superfamily's structure, function, and regulation & control, while giving a brief description of the other forms of GTPases.
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Ras p21 with GTP The
Ras superfamily are monomeric globular proteins, that contain less than
200 amino acid chains.
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Structural changes occur in the Switch I & II regions, these regions interact directly with the g-phosphate of GTP and are considerably altered upon the loss of those interactions giving rise to the inactive form .
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Rab6 GTPase with GDP Rab
is apart of the Ras superfamily.
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Ras superfamily GTPases are fairly inefficient enzymes, they require interactions with GEFs and the GAPs, without the interactions at the effector sites the hydrolysis will not occur.
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Cdc42, Rac, Rho Overlay This
image illustrates the difference in the switch
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The proteins have secondary structure formed by folding of hydrophobic residues in the interior of the protein and polar or charged hydrophilic residues on the outside.
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Left
Fig. shows Ras-GDP, inactive state
Right Fig. shows Ras-GTP, active state
The slight conformational change in Switch I region is able to block the transduction signals to downstream targets.
Mutations occur at the Ras protein residues 12, 13, 59 and 61. Even though residue 61 is not near the binding site, a mutation can prevent interaction with the GTPase Activating Protein (GAP), which is crucial in the hydrolysis of GTP to GDP.
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The interactions of the amino acid residues binding with GDP |
Other Types of GTPases
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Human
guanylate-binding protein 1 (hGBP1) This is an example of a large binding GTPase protein. hGBP1 is considered a dynamin and contains over 300 amino acids. It has a lower nucleotide affinity and a higher GTP turnover rate. |
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SRP (signal-recognition particle)/SR(signal receptor) They function in cotranslational targeting of ribosome complexes to the membrane translocation appartatus. Purple-
GTPase sequence motifs that define the position of the GTP binding site
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Tubulin GTPase Red
is alpha helices The tubulin GTPase hydrolyzes the GTP to GDP and regulates the cytoskeletal membranes
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Initiation
Factor 2
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Initiation
Factor 2 with GDP
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The Initiation Factor 2 is a small GTP-binding protein and the IF-2-GTP binds the initiator to the small ribosomal subunit. The IF-2-GTP is hydrolyzed to IF-2-GDP and is dissociated from the small subunit so the large ribosome subunit can join the small subunit.
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1.
www.rpi.edu/dept/bcbp/miolbiochem/MBWeb/mb2/part1/translate.htm
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