Crystal structure of human cytosolic phospholipase A2 reveals a novel topology and catalytic mechanism.
Cytosolic phospholipase A2 initiates the biosynthesis of prostaglandins, leukotrienes, and platelet-activating factor (PAF), mediators of the pathophysiology of asthma and arthritis. Here, we report the X-ray crystal structure of human cPLA2 at 2.5 A. cPLA2 consists of an N-terminal calcium-dependent lipid-binding/C2 domain and a catalytic unit whose topology is distinct from that of other lipases. An unusual Ser-Asp dyad located in a deep cleft at the center of a predominantly hydrophobic funnel selectively cleaves arachidonyl phospholipids. The structure reveals a flexible lid that must move to allow substrate access to the active site, thus explaining the interfacial activation of this important lipase.
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D020134:Catalytic Domain / Q000235:genetics*; D006224:Cricetinae; D018360:Crystallography, X-Ray; D003600:Cytosol / Q000201:enzymology; D006801:Humans; D006867:Hydrolases / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D010741:Phospholipases A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D054467:Phospholipases A2; D010743:Phospholipids / Q000378:metabolism; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012997:Solvents