Membrane topology of human AGPAT3 (LPAAT3).
Integral membrane lysophospholipid acyltransferases (AT) are involved in many reactions that produce phospholipids and triglycerides. Enzymes that utilize lysophosphatidic acid (LPA) as an acceptor substrate have been termed LPAATs, and several are members of the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) gene family. Amino acid sequence comparisons with other acyltransferases reveal that AGPATs contain four conserved motifs (I-IV), whose invariant residues appear to be important for catalysis and/or substrate recognition. Although the enzymatic activities of many AGPATs are known, for many members their structural organization within membranes and their exact biological functions are unclear. Recently, a new function for AGPATs was discovered when it was determined that human AGPAT3/LPAAT3 is involved in the structure and function of the Golgi complex. Here we have determined the topological orientation of human AGPAT3/LPAAT3. AGPAT3/LPAAT3 possesses two transmembrane domains, one of which separates motifs I and II, which are thought to form a functional unit that is critical for enzymatic activity. This is a surprising result but similar to a recent study on the topology of human LPAAT 1. The data is consistent with a structural arrangement in which motif I is located in the cytoplasm and motif II is in the endoplasmic reticulum and Golgi lumen, suggesting a different model for AGPAT3/LPAAT3's enzymatic mechanism.
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
John A
JA
Schmidt
Griselda Metta
GM
Yvone
William J
WJ
Brown
D000217:Acyltransferases / Q000737:chemistry / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000201:enzymology*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D004721:Endoplasmic Reticulum / Q000201:enzymology; D006801:Humans; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase