GAP (GTPase-activating proteins)

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GTPase-activating proteins (GAP) otherwise known as GTPase-accelerating proteins are a family of regulatory proteins which bind to activated G-proteins in order to stimulate GTPase activity [1]. GAPs also known as RGS proteins are essential in regulating G protein activity, which is important as they control many cellular processes such as transduction of signalling from the G protein-coupled receptor[2]. GAPs function in these processes is to turn off the activity of G proteins, making it produce an opposite effect to guanine nucleotide exchange factors (GEFs)[3]

Contents

Mechanism

GAP proteins are closely linked to the activity of G-protein coupled receptors. The activity of these G-proteins is a result of them binding guanosine triphosphate (GTP). The G-proteins can hydrolyse bound GTP to GDP and release it, by breaking a phosphate bond, however not very effectively so it is a slow process. This results in a reduction of activity for G-protein coupled receptors and their corresponding processes as it takes longer for them to return to their initial state. GAP proteins therefore make the bound GTP a better target for nucleophilic attack by water, by altering the charge distribution and lowering the transition state [4], making it a more reactive substrate and thus speeding up hydrolysis. By doing this it allows G-protein coupled receptors to be activated more frequently within the cell[5]

Classification

Monomeric

GAPs that act on small GTP-binding proteins of the Ras family, have conserved structures and use similar mechanisms.

Heterotrimeric

GAPs that act on alpha subunits of heterotrimeric G proteins, these GAPs belong to the RGS protein family [6].

References

 
  1. Krauss, G. Biochemistry of signal transduction and regulation.Biochemistry and molecular biology education. 2008;36:5:235
  2. Kimple, A.J. Structural Determinants of G-protein α Subunit Selectivity by Regulator of G-protein Signaling 2 (RGS2). The Journal of Biological Chemistry. 2009;284:19402-19411
  3. Krendel,M. Nucleotide Exchange Factor GEF-H1 Mediates Cross-Talk between Microtubules and the Actin Cytoskeleton. Nature Cell Biology. 2002;4:294–301.
  4. Kötting, C. et al. Time-Resolved FTIR Studies Provide Activation Free Energy, Activation Enthalpy and Activation Entropy for GTPase Reactions. Chemical Physics. 2004;307:227–232.
  5. Scheffzek, K. et al. The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants. Science. 1997;277:333–338.
  6. Das S, Ghosh R, Maitra U. Eukaryotic translation initiation factor 5 functions as a GTPase-activating protein. Journal of biological chemistry. 2001; 276: 6720-6726.

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