BIOTECH100
A Resource Guide to Investing in Biotechnology
Directory - Encyclopedia - Stock Index - Pipeline Drugs 

Biotechnology Encyclopedia

GTPase

GTPases are a large family of enzymes that can bind and hydrolyze GTP. The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases. GTPases play an important role in:

Mechanism of GTP hydrolysis

The hydrolysis of the ³ phosphate of GTP supposedly occurs by the SN2 mechanism (see nucleophilic substitution) via a pentavalent intermediate state depending on Mg2+.

Insert image here

Regulatory GTPases

Regulatory GTPases, also called the GTPase superfamily, are GTPases used for regulation of other biochemical processes. Most prominent among the regulatory GTPases are the G proteins.

GTP switch

All regulatory GTPases have a common mechanism that enables them to switch a signal transduction chain on and off. Throwing the switch is performed by the unidirectional change of the GTPase from the active, GTP-bound form to the inactive, GDP-bound form by hydrolysis of the GTP through intrinsic GTPase-activity, effectively switching the GTPase off. This reaction is initiated by GTPase-activating proteins (GAPs), coming from another signal transduction pathway. It can be reverted (switching the GTPase on again) by Guanine nucleotide exchange factors (GEFs), which cause the GDP to dissociate from the GTPase, leading to its association with a new GTP. This closes the cycle to the active state of the GTPase; the irreversible hydrolysis of the GTP to GDP forces the cycle to run only in one direction. Only the active state of the GTPase can transduce a signal to a reaction chain.

Switch regulation

The efficiency of the signal transduction via a GTPase depends on the ratio of active to inactive GTPase. That equals


\frac {\mbox{GTPase}*\mbox{GTP}} {\mbox{GTPase}*\mbox{GDP}} = \frac {k_\mbox{diss.GDP}} {k_\mbox{diss.GTP}}

with kdiss.GDP being the dissociation constant of GDP, and kcat.GTP the hydrolysis constant of GTP for the specific GTPase. Both constants can be modified by special regulatory proteins.
The amount of active GTPase can be changed in several ways :

  1. Acceleration of GDP dissociation by GEFs speeds up the building of active GTPase.
  2. Inhibition of GDP dissociation by guanine nucleotide dissociation inhibitors (GDIs) slows down the building of active GTPase.
  3. Acceleration of GTP hydrolysis by GAPs reduces the amount of active GTPase.
  4. GTP analogues like ³-S-GTP, ²,³-methylene-GTP, and ²,³-imino-GTP that cannot be hydrolized fixate the GTPase in its active state.

Heterotrimeric G proteins

These G proteins are made from three subunits, with the G domain located on the largest one (the ± unit); together with the two smaller subunits ( and ³ units), they form a tightly associated protein complex. ± and ³ unit are associated with the membrane by lipid anchors. Heterotrimeric G proteins act as the specific reaction partners of G protein-coupled receptors. The GTPase is normally inactive. Upon receptor activation, the intracellular receptor domain activates the GTPase, which in turn activates other molecules of the signal transduction chain, either via the ± unit or the ²³ complex. Among the target molecules of the active GTPase are adenylate cyclase and ion channels. The heterotrimeric G proteins can be classified by sequence homology of the ± unit into four families:

  1. Gs family. These G proteins are used in the signal transduction of taste and smell. They always use the activation of adenylate cyclase as the next step in the signal chain. Their function is permanently activated by the cholera toxin, which is the cause of the fatal effects of infection with Vibrio cholerae.
  2. Gi family. The i stands for inhibition of the adenylate cyclase; another effector molecule for this protein family is phospholipase C. Also, Gt and Gg proteins are summarized under this label due to sequence homologies. Gt proteins, aka transducin, is used in the light recognition pathway in retina cells. Gg protein occurs in the taste recognition for bitter. Most Gi protein family members can be inhibited by the pertussis toxin of Bortedella pertussis.
  3. Gq family. These proteins usually have phospholipase C as effector protein.
  4. G12 family. These G proteins can be activated by thromboxan receptors and thrombin receptors. Their effector proteins are unknown.

By combination of different ±, ² and ³ subunits, a great variety (>1.000) of G proteins can be produced.

Activation cycle of heterotrimeric G proteins

In the basic state, the G-GDP-G²³ complex and the receptor that can activate it are separately associated with the membrane. On receptor activation, the receptor becomes highly affine for the G protein complex. On binding with the complex, GDP dissociates from the complex; the free complex has a high affinity for GTP. Upon GTP binding, both G-GTP and G²³ separate from both the receptor and from each other. Depending on the lifetime of the active state of the receptor, it can activate more G proteins this way.
Both G-GTP and G²³ can now activate separate effector molecules and activate them, thus sending the signal further down the signal reaction chain. Once the intrinsic GTPase activity of the ± unit has hydrolyzed the GTP to GDP, the two parts can reassociate to the original, inactive state. The speed of the hydrolysis reaction works as an internal clock for the length of the signal.

The Ras GTPase superfamily

These are small momomeric proteins homologous to Ras. They are also called as small GTPases. The Ras superfamily is further divided into five subfamily: Ras, Rho, Rab, Arf and Ran.

Translation factor family

These GTPases play an important role in initiation, elongation and termination of protein biosynthesis. Fill in more!

Translocation factors

See signal recognition particle (SRP).

See also : biochemistry - G-protein coupled receptors


 
Biotech100 Index
What are the Requirements to be listed in the Biotech100 Index?
 Biotech100 list of companies
Pipeline drugs for the Biotech100


Clinical Trials
What is a Clinical Trial?
Phase I ,-- Phase II, -- PhaseIII
What is Randomized Control?
 What is a Double Blind Experiment?
What is the role of the FDA?


Investing in Stocks
Small Cap Stocks
Stocks and Bonds
Biotech100 Index


Sponsored Links


Careers and Employment
Biotechnology and Pharmaceutical
What are the Fastest Growing Careers?

Key Biotech Terms


Google
 
Web www.biotech100.com
SEARCH THE BIOTECH100 WEBSITE
  
     

 
All text is available under the terms of the GNU Free Documentation License (see Copyrights for details). Disclaimers. Wikipedia is powered by MediaWiki, an open source wiki engine..
 


Copyright 2005 BIOTECH100.COM. All rights reserved.

email: info@biotech100.com