General and versatile autoinhibition of PLC isozymes.
Phospholipase C (PLC) isozymes are directly activated by heterotrimeric G proteins and Ras-like GTPases to hydrolyze phosphatidylinositol 4,5-bisphosphate into the second messengers diacylglycerol and inositol 1,4,5-trisphosphate. Although PLCs play central roles in myriad signaling cascades, the molecular details of their activation remain poorly understood. As described here, the crystal structure of PLC-beta2 illustrates occlusion of the active site by a loop separating the two halves of the catalytic TIM barrel. Removal of this insertion constitutively activates PLC-beta2 without ablating its capacity to be further stimulated by classical G protein modulators. Similar regulation occurs in other PLC members, and a general mechanism of interfacial activation at membranes is presented that provides a unifying framework for PLC activation by diverse stimuli.
Hicks
Stephanie N
SN
Department of Pharmacology, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Jezyk
Mark R
MR
Gershburg
Svetlana
S
Seifert
Jason P
JP
Harden
T Kendall
TK
Sondek
John
J
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054801:Phosphoinositide Phospholipase C / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D054799:Phospholipase C beta / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D054803:Phospholipase C delta / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D007527:Isoenzymes; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; D054799:Phospholipase C beta; D054803:Phospholipase C delta; C423320:phospholipase C epsilon; D019204:GTP-Binding Proteins