cd13361

Phospholipase C-beta (PLC-beta) pleckstrin homology (PH) domain

CDD entry
Member databaseCDD
CDD typedomain
Short namePH_PLC_beta
SetPH-like

Description

PLC-beta (PLCbeta) is regulated by heterotrimeric G protein-coupled receptors through their C2 domain and long C-terminal extension which forms an autoinhibitory helix. There are four isoforms: PLC-beta1-4. The PH domain of PLC-beta2 and PLC-beta3 plays a dual role, much like PLC-delta1, by binding to the plasma membrane, as well as the interaction site for the catalytic activator. However, PLC-beta binds to the lipid surface independent of PIP2. PLC-beta1 seems to play unspecified roles in cellular proliferation and differentiation. PLC-beta consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves, a C2 domain and a C-terminal PDZ. Members of the Rho GTPase family (e.g., Rac1, Rac2, Rac3, and cdc42) have been implicated in their activation by binding to an alternate site on the N-terminal PH domain. A basic amino acid region within the enzyme's long C-terminal tail appears to function as a Nuclear Localization Signal for import into the nucleus. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). 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.the plasma membrane, but only a few (less than 10%) display strong specificity in binding inositol phosphates. 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 kinases, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, cytoskeletal associated molecules, and in lipid associated enzymes.
[4, 9, 5, 1, 6, 11, 12, 7, 2, 10, 14, 13, 8, 3]

References

1.Multiple roles of pleckstrin homology domains in phospholipase Cbeta function. Philip F, Guo Y, Scarlata S. FEBS Lett 531, 28-32, (2002). PMID: 12401198

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.Crystal structure of Rac1 bound to its effector phospholipase C-beta2. Jezyk MR, Snyder JT, Gershberg S, Worthylake DK, Harden TK, Sondek J. Nat. Struct. Mol. Biol. 13, 1135-40, (2006). View articlePMID: 17115053

5.Structure of the high affinity complex of inositol trisphosphate with a phospholipase C pleckstrin homology domain. Ferguson KM, Lemmon MA, Schlessinger J, Sigler PB. Cell 83, 1037-46, (1995). View articlePMID: 8521504

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

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

8.Multiple roles of phosphoinositide-specific phospholipase C isozymes. Suh PG, Park JI, Manzoli L, Cocco L, Peak JC, Katan M, Fukami K, Kataoka T, Yun S, Ryu SH. BMB Rep 41, 415-34, (2008). View articlePMID: 18593525

9.An autoinhibitory helix in the C-terminal region of phospholipase C-β mediates Gαq activation. Lyon AM, Tesmer VM, Dhamsania VD, Thal DM, Gutierrez J, Chowdhury S, Suddala KC, Northup JK, Tesmer JJ. Nat Struct Mol Biol 18, 999-1005, (2011). PMID: 21822282

10.The correlation between multidomain enzymes and multiple activation mechanisms--the case of phospholipase Cβ and its membrane interactions. Weinstein H, Scarlata S. Biochim. Biophys. Acta 1808, 2940-7, (2011). View articlePMID: 21906583

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

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

13.Structure, regulation, and function of phospholipase C isozymes. Fukami K. J Biochem 131, 293-9, (2002). PMID: 11872156

14.Subtype-specific roles of phospholipase C-β via differential interactions with PDZ domain proteins. Kim JK, Lim S, Kim J, Kim S, Kim JH, Ryu SH, Suh PG. Adv Enzyme Regul 51, 138-51, (2011). PMID: 21035486

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