Crystal structure of human cytosolic phospholipase A2 reveals a novel topology and catalytic mechanism

• Published in: Cell 1999-04, Vol.97 (3), p.349-360
• Main Authors: Dessen, A, Tang, J, Schmidt, H, Stahl, M, Clark, J D, Seehra, J, Somers, W S
• Format: Article
• Language: English
• Subjects: Animals; Arachidonic Acid - metabolism; Binding Sites - genetics; Calcium - metabolism; Catalytic Domain - genetics; CHO Cells; Cricetinae; Crystallography, X-Ray; Cytosol - enzymology; Humans; Hydrolases - chemistry; Hydrolases - metabolism; Molecular Sequence Data; Phospholipases A - chemistry; Phospholipases A - genetics; Phospholipases A - metabolism; Phospholipases A2; Phospholipids - metabolism; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Solvents
• ISSN: 0092-8674
• DOI: 10.1016/s0092-8674(00)80744-8

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.