Delineation of two functionally distinct domains of cytosolic phospholipase A2, a regulatory Ca(2+)-dependent lipid-binding domain and a Ca(2+)-independent catalytic domain.

Nalefski, Eric A.; Sultzman, Lisa A.; Martin, David; Kriz, Ronald; Towler, P.; Knopf, John L.; Clark, James D.

doi:10.1016/s0021-9258(17)32440-7

Cited by 330 publications

(65 citation statements)

References 68 publications

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“…CRP molecules are known from electron microscopy to form ordered 2D arrays at surfaces and this effect is likely to occur on the lipid bilayer, as has been shown for Annexin V [50]. A number of proteins, including phospholipase Cβ, phospholipase A2, rabphilin 3A and synaptotagmin I, interact with cell membranes in a calcium-dependent manner via their Greek-key C2 domains [51][52][53][54]. Adjacent bound CRP molecules may present multiple binding sites via the A face furrows and central pore region for the head groups of C1q arms, providing a mechanism for head group cross-linking that is known to be involved in Fc activation of C1q by immune complexes and an explanation for the observed requirement that CRP be aggregated to the level of dimers or trimers for in vitro activation of complement.…”

Section: A Model For Crp-mediated Binding Of C1q To the Cell Surfacementioning

confidence: 95%

The physiological structure of human C-reactive protein and its complex with phosphocholine

1999

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The structure shows how large ligands containing PC may be bound by CRP via a phosphate oxygen that projects away from the surface of the protein. Multipoint attachment of one planar face of the CRP molecule to a PC-bearing surface would leave available, on the opposite exposed face, the recognition sites for C1q, which have been identified by mutagenesis. This would enable CRP to target physiologically and/or pathologically significant complement activation. The hydrophobic pocket adjacent to bound PC invites the design of inhibitors of CRP binding that may have therapeutic relevance to the possible role of CRP in atherothrombotic events.

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Section: A Model For Crp-mediated Binding Of C1q To the Cell Surfacementioning

confidence: 95%

The physiological structure of human C-reactive protein and its complex with phosphocholine

1999

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“…The domain was shown to bind all negatively charged phospholipids as well as syntaxin . The cPLA2 (Nalefski et al, 1994;Nalefski et al, 1997), PKCp (Shao et al, 1996) and Nedd4 (Plant et al, 1997) C2-domains also bind phospholipids in a Ca2+-dependent manner, although cPLA2 binds to neutral phospholipids (Daveltov and Siidhof 1993;Nalefski et al, 1998) and PKCp does not exhibit Ca2+-dependent syntaxin 1 binding. These facts reflect the functional diversity among C2-domains.…”

Section: -Expression Of Rpgripmentioning

confidence: 99%

Identification of a novel protein interacting with RPGR

Boylan

2000

Human Molecular Genetics

113

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A novel protein, called RPGRIP, has been identified as interacting with the RPGR protein, which is mutated in a severe form of human retinal degeneration, X-linked retinitis pigmentosa (RP3 type). The bovine RPGRIP was identified initially by screening for RPGR-interacting proteins with a bovine retina cDNA library using the yeast two-hybrid system. The specificity of the interaction was confirmed by co-immunoprecipitation of in vitro translated protein and using RPGR mutants. The human RPGRIP gene was isolated and shown to be expressed in retina and testis. Human RPGRIP spans a genomic interval of 34 kb, and consists of 15 exons, some of which are alternatively spliced. It was mapped using monochromosomal and radiation hybrid cell lines to chromosomal region 14q11. The function of RPGRIP is unknown; it shows no homology to proteins of known function, although it is predicted to form two coiled-coil domains at the N-terminus. RPGRIP is a strong candidate gene for causing human retinal degeneration.

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“…The mechanism by which cPLA 2 , a key enzyme in the inflammatory cascade of arachidonic acid, binds to its phospholipid substrate has been reported (34 -37). It is widely accepted that cPLA 2 hydrolyzes preferentially aggregated phospholipids within the membrane/water interface rather than a monomeric form (27). The critical role of calcium in membrane penetration of cPLA 2 after binding has been demonstrated (34 -37).…”

Section: Discussionmentioning

confidence: 99%

“…Maximal activation of cPLA 2 is obtained after phosphorylation of Ser-505 via the MAPK pathway and mobilization of intracellular calcium (24)(25)(26). Calcium activation is mediated by a calcium-dependent lipid-binding domain that triggers the translocation of the enzyme, which makes the catalytic domain accessible to the phospholipid substrate (27). However, other mechanisms might be involved in cPLA 2 activation.…”

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confidence: 99%

Sphingolipids and cholesterol modulate membrane susceptibility to cytosolic phospholipase A2

Klapisz

Masliah

Béréziat

et al. 2000

Journal of Lipid Research

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Modulation of cytosolic phospholipase A 2 (cPLA 2 ) activity by sphingomyelin (SPH), ceramide (Cer), and cholesterol (Chol) was investigated in CHO-2B cells activated by the calcium ionophore A23187 and epinephrine. Chol depletion of CHO-2B cells by treatment with methyl-␤cyclodextrin (5 m M ) resulted in the inhibition of the release of arachidonic acid whereas the restoration of the level by Chol-loaded cyclodextrin relieved inhibition. Conversion of CHO-2B cellular SPH to Cer by Staphylococcus aureus sphingomyelinase enhanced endogenous cPLA 2 activation as well as uptake by cells of C2-and C6-ceramide analogs. These results were confirmed in vitro with purified human recombinant cPLA 2 acting on a model phospholipid substrate. The enzyme activity was inhibited by SPH but reactivated by Cer as well as by Chol added to glycerophospholipid liposomal substrates containing SPH. The results of this study, which combine in situ and in vitro experimental approaches, indicate that membrane microdomains enriched in SPH and Chol play a role in the modulation of the activity of cPLA 2 and in arachidonic acid-derived mediator production. -Klapisz, E., J. Masliah, G. Béréziat, C. Wolf, and K. S. Koumanov. Sphingolipids and cholesterol modulate membrane susceptibility to cytosolic phospholipase A 2 .

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Delineation of two functionally distinct domains of cytosolic phospholipase A2, a regulatory Ca(2+)-dependent lipid-binding domain and a Ca(2+)-independent catalytic domain.

Cited by 330 publications

References 68 publications

The physiological structure of human C-reactive protein and its complex with phosphocholine

The physiological structure of human C-reactive protein and its complex with phosphocholine

Identification of a novel protein interacting with RPGR

Sphingolipids and cholesterol modulate membrane susceptibility to cytosolic phospholipase A2

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