cd01224

Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain

CDD entry
Member databaseCDD
CDD typedomain
Short namePH_Collybistin_ASEF
SetPH-like

Description

Collybistin (also called PEM2) is homologous to the Dbl proteins ASEF (also called ARHGEF4/RhoGEF4) and SPATA13 (Spermatogenesis-associated protein 13; also called ASEF2). It activates CDC42 specifically and not any other Rho-family GTPases. Collybistin consists of an SH3 domain, followed by a RhoGEF/DH and PH domain. In Dbl proteins, the DH and PH domains catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors. It induces submembrane clustering of the receptor-associated peripheral membrane protein gephyrin, which is thought to form a scaffold underneath the postsynaptic membrane linking receptors to the cytoskeleton. It also acts as a tumor suppressor that links adenomatous polyposis coli (APC) protein, a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of beta-catenin, to Cdc42. Autoinhibition of collybistin is accomplished by the binding of its SH3 domain with both the RhoGEF and PH domains to block access of Cdc42 to the GTPase-binding site. Inactivation promotes cancer progression. 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.
[1, 5, 10, 7, 3, 2, 8, 6, 4, 9]

References

1.The crystal structure of Cdc42 in complex with collybistin II, a gephyrin-interacting guanine nucleotide exchange factor. Xiang S, Kim EY, Connelly JJ, Nassar N, Kirsch J, Winking J, Schwarz G, Schindelin H. J. Mol. Biol. 359, 35-46, (2006). View articlePMID: 16616186

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

3.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

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.Crystal structure of the rac activator, Asef, reveals its autoinhibitory mechanism. Murayama K, Shirouzu M, Kawasaki Y, Kato-Murayama M, Hanawa-Suetsugu K, Sakamoto A, Katsura Y, Suenaga A, Toyama M, Terada T, Taiji M, Akiyama T, Yokoyama S. J. Biol. Chem. 282, 4238-42, (2007). View articlePMID: 17190834

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

7.Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin. Kins S, Betz H, Kirsch J. Nat Neurosci 3, 22-9, (2000). PMID: 10607391

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

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

10.Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression. Mitin N, Betts L, Yohe ME, Der CJ, Sondek J, Rossman KL. Nat. Struct. Mol. Biol. 14, 814-23, (2007). View articlePMID: 17704816

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