CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector R588 Current Biology, Vol 9 No 16 11. SMART database: http://coot.embl- 24. Tsiokas L, Kim E, Arnould T, Sukhatme VP, formation occurs as part of a ‘two- heidelberg.de/SMART/ Walz G: Homo- and heterodimeric 12. Sugita S, Ichchenko K, Khvotchev M, interactions between the gene products hit’ process in which inactivation of Südhof TC: α-Latrotoxin receptor of PKD1 and PKD2. Proc Natl Acad Sci both alleles of ADPKD genes leads CIRL/latrophilin 1 (CL1) defines an USA 1997, 94:6965-6970. to abnormalities of cell proliferation, unusual family of ubiquitous G-protein- 25. Brown N, Lai J: Consensus. linked receptors. J Biol Chem 1998, http://www.bork.embl- apoptosis and differentiation [1]. Of 273:32715-32724. heidelberg.de/Alignment/consensus.html ADPKD cases, 85% are due to 13. Krasnoperov V, Bittner MA, Holz RW, 26. Rost B, Sander C: Prediction of protein Chepurny O, Petrenko AG: Structural structure at better than 70% accuracy. mutations in the PKD1 gene, which α requirements for -latrotoxin binding and J Mol Biol 1993, 232:584-599. encodes a 4,302 amino acid protein, α-latrotoxin-stimulated secretion. J Biol Chem 1999, 274:3590-3596. polycystin-1 (PKD1), of unknown 14. Krasnoperov V, Bittner MA, Beavis R, Addresses: *National Center for function. Comparison of the PKD1 Kuang Y, Salnikow KV, Chepurny OG, Little Biotechnology Information, National Library of sequence with homologous AR, Plotnikov AN, Wu D, Holz RW, et al.: Medicine, National Institutes of Health, α-Latrotoxin stimulates exocytosis by Bethesda Maryland 20894, USA. sequences from mouse and Fugu the interaction with a neuronal G- †MEMOREC Stoffel GmbH, Stöckheimer predicts polycystin-1 to have a large protein-coupled receptor. Neuron 1997, Weg 1, D-50829 Köln, Germany. ‡European 18:925-937. extracellular region of 3,000 amino 15. Ichtchenko K, Bittner MA, Krasnoperov V, Molecular Biology Laboratory, acid residues, a region containing Little AR, Chepurny O, Holz RW, Petrenko Meyerhofstrasse 1, D-69012 Heidelberg, 11 putative transmembrane AG: A novel ubiquitously expressed α- Germany. §Max-Delbrück-Center for Molecular latrotoxin receptor is a member of the Medicine, D-13125 Berlin-Buch, Germany. segments and a short intracellular CIRL family of G-protein-coupled E-mail: [email protected] tail [2]. A well-defined extracellular receptors. J Biol Chem 1999, 274:5491-5498. domain structure is apparent; the 16. Gray JX, Haino M, Roth MJ, Maguire JE, presence of amino-terminal leucine- Jensen PN, Yarme A, Stetler-Stevenson MA, Siebenlist U, Kelly K: CD97 is a processed, The PLAT domain: a rich repeats, a C-type-lectin domain seven-transmembrane, heterodimeric and multiple PKD repeats suggests a receptor associated with inflammation. new piece in the PKD1 role in cell–cell or cell–matrix J Immunol 1996, 157:5438-5447. 17. Watnick TJ, Piontek KB, Cordal TM, Weber puzzle interactions (Figure 1) [3]. So far, no H, Gandolph MA, Qian F, Lens XM, extracellular ligands of polycystin-1 Neumann HPH, Germino GG: An unusual pattern of mutation in the duplicated Alex Bateman* and have been identified. Of the portion of PKD1 is revealed by use of a Richard Sandford† intracellular regions of PKD1, novel strategy for mutation detection. functional properties have been Hum Mol Genet 1997, 6:1473-1481. 18. Sandford R, Sgotto B, Aparicio S, Brenner Autosomal dominant polycystic defined only for the short 198 amino S, Vaudin M, Wilson RK, Chissoe S, Pepin kidney disease (ADPKD) has a acid carboxy-terminal region, which K, Bateman A, Chothia C, et al.: Comparative analysis of the polycystic prevalence of 1 in 800 of the world’s contains a predicted coiled-coil kidney disease 1 (PKD1) gene reveals an population and accounts for 10% of domain. These include a direct integral membrane glycoprotein with multiple evolutionary conserved individuals who require renal interaction with the carboxyl domains. Hum Mol Genet 1997, replacement therapy, either dialysis terminus of the protein encoded by 6:1483-1489. or transplantation. Renal cyst PKD2, polycystin-2 [4], activation of 19. Moy GW, Mendoza LM, Schultz JR, Swanson WJ, Glabe CG, Vacquier VD: The sea urchin sperm receptor for egg jelly is a modular protein with extensive Figure 1 homology to the human polycystic kidney disease protein, PKD1. J Cell Biol 1996, 133:809-817. PKD1_HUMAN (P98161) 20. Trimmer JS, Schackmann RW, Vacquier VD: 4303 aa Monoclonal antibodies increase intracellular Ca2+ in sea urchin spermatozoa. Proc Natl Acad Sci USA LIPP_HUMAN (P16233) LOX1_HUMAN (P16050) PHLC_CLOPE (P15310) 1986, 83:9055-9059. 465 aa 661 aa 398 aa 21 Lu W, Peissel B, Babakhanlou H, Pavlova A, Geng, L, Fan X, Larson C, Brent G, Zhou J: Perinatal lethality with kidney and PLAT domain REJ domain Leucine-rich repeats pancreas defects in mice with a targetted and flanking domains Zinc-dependent phospholipase C Pkd1 mutation. Nat Genet 1997, PKD domain Lipase 17: 179-181. C-type lectin Lipoxygenase 22. Hughes J, Ward CJ, Aspinwall R, Butler R, Harris PC: Identification of a human LDL-A domain Transmembrane region homologue of the sea urchin receptor for Current Biology egg jelly: a polycystic kidney disease-like protein. Hum Mol Genet 1999, 8:543-549. Schematic diagram of the domain PF00560; C-type lectin, PF00059; LDL-A, 23. Mochizuki T, Wu G, Hayashi T, organisation of PLAT domain proteins. PF00057; PKD domains, PF00801; PLAT Xenophontos SL, Veldhuisen B, Saris JJ, Information and alignments for each of the domain, PF01477; lipoxygenase, PF00305; Reynolds DM, Cai Y, Gavow PA, Pierides A, domains can be found in the Pfam database Zn2+-dependent phospholipase C, et al.: PKD2, a gene for polycystic kidney [14,15] using the following identifiers or PF00882; lipase, PF00151. Abbreviation: disease that encodes an integral accession numbers: leucine-rich repeats, aa, amino acids. membrane protein. Science 1996, 272:1339-1342. Magazine R589 transcription factor AP-1 [5] and The current model of polycystin-1 expectation-value (E-value) threshold activation of heterotrimeric topology suggests that there are four of 0.001 [7]. For each of the four G proteins [6]. The last of these intracellular regions that are large intracellular regions, PSI-BLAST occurs via a motif present in one of enough to contain a discrete protein returned the known PKD1 polycystin-1’s most highly conserved domain. These regions are between orthologues from human, mouse and regions. Polycystin-1 may therefore transmembrane (TM) helices TM1 Fugu. Only one region returned act as a cell-surface receptor or form and TM2 (residues 3,096–3,280), TM3 significant matches with PSI-BLAST. part of a large membrane-associated and TM4 (residues 3,344–3,558), TM5 The first intracellular region between complex that is capable of signaling and TM6 (residues 3,603–3,668) and TM1 and TM2, which represents the by several different pathways to the carboxy-terminal region after most strongly conserved sequence control cell proliferation and TM11 (residues 4,105–4,302). The region of PKD1 between human and differentiation. To further aid the high sequence conservation seen in Fugu [2], was found to match to 67 understanding of this enigmatic these regions between the human other sequences in SWISS-PROT protein, we have surveyed all the and Fugu polycystin-1 suggest that version 37 and TrEMBL version 9 intracellular regions for potential they are functionally important. We [8]. These sequences include domains that may suggest novel have used each of these regions as a mammalian lipoxygenases, functions and identify further query for the sequence comparison triacylglycerol lipase and lipoprotein avenues for experiment. program PSI-BLAST, using an lipase. The common feature found in Figure 2 10 20 30 40 50 60 70 80 90 ||||||||| PKD1_HUMAN/3118-3223 F K Y E I L V K T G W . G R G S G T T A H V G I M L Y G V D S R S G H R H L D G D R . A F H R N S L D I F R I A T P H S L G S V W K I R V W H D N K G L . O42181/3249-3364 F K Y E I Q V K T G W . S R G A G T T A H V G I S L Y G R E S R S G H R H L D S R G . S F A R N A L D I F H I A T D T S L G N V W K M R I W H D N K G L . YS89_CAEEL/1333-1452 Y M Y V I A V E T G Y . R M F A T T D S T I C F N L S G N E G D Q I F R S F R S E E D G N W E . F P F S W G T T D R F V M T T A F P L G E L E Y M R L W L D D A G L D . LOX1_HUMAN/1-110 G L Y R I R V S T G A . S L Y A G S N N Q V Q L W L V G Q H G E A A L G K R L W . P A R G K E T E L K V E V P E Y L G P L L F V K L R K R H L L K . LOX2_RAT/1-111 G V Y R I R V S T G D .