cd01225

Cloned out of library/PAK-interactive exchange factor pleckstrin homology (PH) domain

CDD entry
Member databaseCDD
CDD typedomain
Short namePH_Cool_Pix
SetPH-like

Description

There are two forms of Pix proteins: alpha Pix (also called Rho guanine nucleotide exchange factor (GEF) 6/90Cool-2) and beta Pix (GEF7/p85Cool-1). betaPix contains an N-terminal SH3 domain, a RhoGEF/DH domain, a PH domain, a GIT1 binding domain (GBD), and a C-terminal coiled-coil (CC) domain. alphaPix differs in that it contains a calponin homology (CH) domain, which interacts with beta-parvin, N-terminal to the SH3 domain. alphaPix is an exchange factor for Rac1 and Cdc42 and mediates Pak activation on cell adhesion to fibronectin. Mutations in alphaPix can cause X-linked mental retardation. alphaPix also interacts with Huntington's disease protein (htt), and enhances the aggregation of mutant htt (muthtt) by facilitating SDS-soluble muthtt-muthtt interactions. The DH-PH domain of a Pix was required for its binding to htt. In the majority of Rho GEF proteins, the DH-PH domain is responsible for the exchange activity. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.
[6, 5, 7, 9, 3, 4, 8, 10, 2, 1, 11]

References

1.Pleckstrin homology (PH) domains and phosphoinositides. Lemmon MA. Biochem. Soc. Symp. 81-93, (2007). PMID: 17233582

2.Pleckstrin homology (PH) like domains - versatile modules in protein-protein interaction platforms. Scheffzek K, Welti S. FEBS Lett. 586, 2662-73, (2012). View articlePMID: 22728242

3.Regulation of the Cool/Pix proteins: key binding partners of the Cdc42/Rac targets, the p21-activated kinases. Feng Q, Albeck JG, Cerione RA, Yang W. J Biol Chem 277, 5644-50, (2002). PMID: 11741931

4.Membrane targeting by pleckstrin homology domains. Cozier GE, Carlton J, Bouyoucef D, Cullen PJ. Curr. Top. Microbiol. Immunol. 282, 49-88, (2004). PMID: 14594214

5.Biochemical characterization of the Cool (Cloned-out-of-Library)/Pix (Pak-interactive exchange factor) proteins. Baird D, Feng Q, Cerione RA. Meth. Enzymol. 406, 58-69, (2006). View articlePMID: 16472649

6.alpha Pix enhances mutant huntingtin aggregation. Eriguchi M, Mizuta H, Luo S, Kuroda Y, Hara H, Rubinsztein DC. J Neurol Sci 290, 80-5, (2010). PMID: 19969308

7.The Cbl proteins are binding partners for the Cool/Pix family of p21-activated kinase-binding proteins. Flanders JA, Feng Q, Bagrodia S, Laux MT, Singavarapu A, Cerione RA. FEBS Lett 550, 119-23, (2003). PMID: 12935897

8.Pleckstrin homology domains: not just for phosphoinositides. Lemmon MA. Biochem. Soc. Trans. 32, 707-11, (2004). PMID: 15493994

9.Pak to the future. Bagrodia S, Cerione RA. Trends Cell Biol. 9, 350-5, (1999). View articlePMID: 10461188

10.Pleckstrin homology domains: two halves make a hole? Lemmon MA. Cell 120, 574-6, (2005). View articlePMID: 15766521

11.Signal-dependent membrane targeting by pleckstrin homology (PH) domains. Lemmon MA, Ferguson KM. Biochem J 350 Pt 1, 1-18, (2000). PMID: 10926821

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