Novel Mammalian Group XII Secreted Phospholipase A₂Lacking Enzymatic Activity^,

Abstract

An increasing number of mammalian secreted phospholipases A(2) (sPLA(2)s) has been identified over the past few years. Here, we report the identification and recombinant expression of a novel sPLA(2)-like protein in mouse and human species that has been called group XIIB (GXIIB). The mature protein has a molecular mass of 19.7 kDa and structural features similar to those of the previously identified GXII sPLA(2), now called GXIIA. Strikingly, the GXIIB sPLA(2) has a mutation in the active site, replacing the canonical histidine by a leucine, suggesting that this sPLA(2) is catalytically inactive. Recombinant expression of human (hGXIIB) and mouse (mGXIIB) sPLA(2)s in Escherichia coli indicates that GXIIB sPLA(2)s display no measurable lipolytic activity on various types of phospholipid substrates. Furthermore, these sPLA(2)-like proteins display relatively weak affinity to phospholipid vesicles. Binding experiments indicate that these proteins are also unable to bind to the well-known M-type sPLA(2) receptor. The RNA tissue distribution of GXIIB sPLA(2)s is distinct from that of other sPLA(2)s including the homologous GXIIA. Strong expression was observed in liver, small intestine, and kidney in both human and mouse species. Interestingly, the expression of the novel sPLA(2) is dramatically decreased in human tumors from the same tissues. The absence of enzymatic activity suggests that the GXIIB sPLA(2)-like proteins probably exert their biological roles by acting as ligands for as yet unidentified receptors.

A new era of secreted phospholipase A2

“…In humans, there is a suggestive association between a PLA2G12A polymorphism and response to anti-vascular endothelial growth factor therapy in patients with exudative age-related macular degeneration ( 144 ). sPLA 2 -XIIB, preferentially expressed in the liver, is catalytically inactive due to the replacement of the catalytic histidine by a leucine residue ( 16 ). Hepatic expression of sPLA 2 -XIIB is induced by the transcription factor HNF-4 ␣ and its coactivator PGC-1 ␣ , and Pla2g12b Ϫ / Ϫ mice display steatohepatitis due to impaired hepatic secretion of VLDL ( 145 ).…”

“…sPLA 2 -III is an atypical sPLA 2 that is more similar to bee venom group III sPLA 2 than to other mammalian sPLA 2 s ( 14 ). Another atypical sPLA 2 -XII subfamily, XIIA and XIIB, has very unique structural and functional features ( 15,16 ), and the preservation of sPLA 2 -XII members from bacteria to human indicates that they emerged early in evolution prior to Eubacteria ( 17 ). Currently known sPLA 2 inhibitors can inhibit conventional sPLA 2 s to various degrees, yet an agent that specifi cally inhibits sPLA 2 -III or -XIIA has not yet become available.…”

Distinct expression pattern of the full set of secreted phospholipases A2 in human colorectal adenocarcinomas: sPLA2-III as a biomarker candidate

“…Human sPLA 2 s have been classified into groups IB, IIA, IID, IIE, IIF, III, V, X, XIIA and XIIB according to their structural properties (Laye and Gill, 2003;Rouault et al, 2003;Murakami et al, 2005;Cummings, 2007). Several of these proteins have recently been proposed either as biomarkers of pathologies (Smith et al, 2003;Mallat et al, 2005;Wootton et al, 2007) or as therapeutic targets (Laye and Gill, 2003;Cummings, 2007;Henderson et al, 2007).…”

Snake Venom Peptides: Promising Molecules with Anti-Tumor Effects

“…PLA2 are low molecular weight proteins with molecular masses ranging from 13-19 kDa that generally require Ca 2+ for their activities [69,70]. Snake venom sPLA2 are secreted enzymes belonging to only two groups that are based on their primary structure and disulfide bridge pattern [68,71,72]. Those of group I are similar to pancreatic sPLA2 present in mammals, were found in venom of Elapidae snakes, while group II PLA2s belong to the Viperidae and are similar to mammals nonpancreatic, inflammatory sPLA2s [73,74].…”