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DH Domain
Class:Cytoskeletal modulation

No ImageThe DH domain is composed of a unique extended bundle of alpha-helices. This bundle is mainly composed of the CR1, CR2, and CR3 regions which each form separate alpha helices that pack together. The CR1 and CR3 regions are solvent exposed until complexed with a Rho GTPase where they then form the primary points of contact. Upon binding of the DH domain of Tiam-1 to Rac-1 the switch I region within the GTP binding pocket of Rac-1 is shifted and binds within a groove formed by the CR1 and CR3 regions within Tiam-1. The switch II region within Rac-1 binds to an even larger area of the DH domain causing residues 59 and 64 in Rac-1 to be displaced. The net effect of these changes is that the Mg2+ ion coordinated to GDP and the P loop which binds the terminal phosphate on GDP is displaced which in turn destabilizes the binding of GDP to Rac-1.

Structure reference:
Worthylake, T. et al. (2000) Nature. 408(6813): 682-688. PDB: 1FOE.

Domain binding and function:
The Dbl homology (DH) or RhoGEF domain consists of an ~ 150 amino acid region that induces Rho family GTPases to displace GDP. This effectively activates the Rho GTPase by allowing binding to GTP, which is in excess over GDP in the cell. The DH domain is invariably proceeded by a pleckstrin homology (PH) domain. While not absolutely required for catalysis of nucleotide exchange, the PH domain appears to greatly increase catalytic efficiency in many cases. Rho proteins control actin dynamics, gene expression, membrane trafficking, growth factor signaling, and cellular transformation. Proteins encoding DH domains (RhoGEFs) also play a role in these events as they function as the primary activators of Rho GTPases. In fact, many RhoGEFs were identified based on their transforming activity, which was abrogated upon disruption of their DH domain.
Examples of Proteins: 
Binding partner
Dbl RhoA/Rac1/Cdc42
p190 RhoGEF RhoA
Tiam-1 Rac1/Cdc42
p115 RhoGEF RhoA

No Image

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