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3.A.3.8.2
Golgi aminophospholipid translocase (flipping from the exofacial to the cytosolic leaflet of membranes), required for vesicle-mediated protein transport from the Golgi and endosomal lumen to the cytoplasm, Gea2p (Pomorski et al., 2003). The system has been reconstituted after purification in proteoliposomes. It flips phosphatidyl serine and phosphatidyl ethanolamine, but not phosphatidylcholine or sphingomyelin (Zhou and Graham, 2009).  Drs2p (ACT3; ATP8A2) is required for phospholipid translocation across the Golgi membrane. It interacts with CDC50 (TC# 8.A.27) (Bryde et al., 2010). Activated by ArfGEF when bound to the C-terminus (Natarajan et al. 2009). The beta-subunit, CDC50A, allows the stable expression, assembly, subcellular localization, and lipid transport activity of the P4-ATPase ATP8A2 (Coleman and Molday, 2011). Timcenko et al. 2019 described the cryo-EM structure of Drs2p-Cdc50p, It is autoinhibited by the C-terminal tail of Drs2p and activated by the lipid phosphatidylinositol-4-phosphate (PI4P). Three structures were solved that represent the complex in an autoinhibited, an intermediate and a fully activated state. The analysis revealed sites of autoinhibition and PI4P-dependent activation. A putative lipid translocation pathway involves a conserved PISL motif in TMS 4 and polar residues of TMSs 2 and 5, in particular Lys1018, in the centre of the lipid bilayer (Timcenko et al. 2019). The enzymatic cycle of P-type ATPases is divided into autophosphorylation and dephosphorylation half-reactions. Unlike most other P-type ATPases, P4-ATPases transport their substrate during dephosphorylation only, i.e. the phosphorylation half-reaction is not associated with transport. To study the structural basis of the distinct mechanisms of P4-ATPases, Timcenko et al. 2021 determined cryo-EM structures of Drs2p-Cdc50p covering multiple intermediates of the cycle. They identified several structural motifs specific to Drs2p and P4-ATPases in general that decrease movements and flexibility of domains as compared to other P-type ATPases. These motifs include the linkers that connect the transmembrane region to the actuator (A) domain, which is responsible for dephosphorylation. Mutation of Tyr380, which interacts with conserved Asp340 of the distinct DGET dephosphorylation loop of P4-ATPases, highlights a functional role of these P4-ATPase specific motifs in the A-domain. Finally, the transmembrane (TM) domain, responsible for transport, also undergoes less extensive conformational changes, which is ensured both by a longer segment connecting TM helix 4 with the phosphorylation site, and possible stabilization by the auxiliary subunit Cdc50p. Collectively these adaptions in P4-ATPases are responsible for phosphorylation becoming transport-independent (Timcenko et al. 2021). The Arf activator, Gea2p (Uniprot P39993, 1459 aas), and Drs2p interact in the Golgi (Chantalat et al. 2004).

Accession Number:P39524
Protein Name:ATC3 aka DRS2 aka YAL026C aka FUN38
Length:1355
Molecular Weight:153845.00
Species:Saccharomyces cerevisiae (Baker's yeast) [4932]
Number of TMSs:8
Location1 / Topology2 / Orientation3: Golgi apparatus1 / Multi-pass membrane protein2
Substrate aminophospholipid

Cross database links:

DIP: DIP-2216N DIP-2216N
RefSeq: NP_009376.1   
Entrez Gene ID: 851207   
Pfam: PF00122    PF00702   
KEGG: sce:YAL026C   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005802 C:trans-Golgi network
GO:0005524 F:ATP binding
GO:0015662 F:ATPase activity, coupled to transmembrane m...
GO:0000287 F:magnesium ion binding
GO:0004012 F:phospholipid-translocating ATPase activity
GO:0005515 F:protein binding
GO:0006754 P:ATP biosynthetic process
GO:0006897 P:endocytosis
GO:0006886 P:intracellular protein transport
GO:0045332 P:phospholipid translocation
GO:0006892 P:post-Golgi vesicle-mediated transport
GO:0000028 P:ribosomal small subunit assembly

References (16)

[1] “DRS1 to DRS7, novel genes required for ribosome assembly and function in Saccharomyces cerevisiae.”  Ripmaster T.L.et.al.   8247005
[2] “The nucleotide sequence of chromosome I from Saccharomyces cerevisiae.”  Bussey H.et.al.   7731988
[3] “Drs2p-dependent formation of exocytic clathrin-coated vesicles in vivo.”  Gall W.E.et.al.   12372257
[4] “Global analysis of protein expression in yeast.”  Ghaemmaghami S.et.al.   14562106
[5] “Cdc50p, a protein required for polarized growth, associates with the Drs2p P-type ATPase implicated in phospholipid translocation in Saccharomyces cerevisiae.”  Saito K.et.al.   15090616
[6] “Quantitative phosphoproteomics applied to the yeast pheromone signaling pathway.”  Gruhler A.et.al.   15665377
[7] “A global topology map of the Saccharomyces cerevisiae membrane proteome.”  Kim H.et.al.   16847258
[8] “A multidimensional chromatography technology for in-depth phosphoproteome analysis.”  Albuquerque C.P.et.al.   18407956
[9] “DRS1 to DRS7, novel genes required for ribosome assembly and function in Saccharomyces cerevisiae.”  Ripmaster T.L.et.al.   8247005
[10] “The nucleotide sequence of chromosome I from Saccharomyces cerevisiae.”  Bussey H.et.al.   7731988
[11] “Drs2p-dependent formation of exocytic clathrin-coated vesicles in vivo.”  Gall W.E.et.al.   12372257
[12] “Global analysis of protein expression in yeast.”  Ghaemmaghami S.et.al.   14562106
[13] “Cdc50p, a protein required for polarized growth, associates with the Drs2p P-type ATPase implicated in phospholipid translocation in Saccharomyces cerevisiae.”  Saito K.et.al.   15090616
[14] “Quantitative phosphoproteomics applied to the yeast pheromone signaling pathway.”  Gruhler A.et.al.   15665377
[15] “A global topology map of the Saccharomyces cerevisiae membrane proteome.”  Kim H.et.al.   16847258
[16] “A multidimensional chromatography technology for in-depth phosphoproteome analysis.”  Albuquerque C.P.et.al.   18407956
Structure:
6PSX   6PSY   6ROH   6ROI   6ROJ     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MNDDRETPPK RKPGEDDTLF DIDFLDDTTS HSGSRSKVTN SHANGYYIPP SHVLPEETID 
61:	LDADDDNIEN DVHENLFMSN NHDDQTSWNA NRFDSDAYQP QSLRAVKPPG LFARFGNGLK 
121:	NAFTFKRKKG PESFEMNHYN AVTNNELDDN YLDSRNKFNI KILFNRYILR KNVGDAEGNG 
181:	EPRVIHINDS LANSSFGYSD NHISTTKYNF ATFLPKFLFQ EFSKYANLFF LCTSAIQQVP 
241:	HVSPTNRYTT IGTLLVVLIV SAMKECIEDI KRANSDKELN NSTAEIFSEA HDDFVEKRWI 
301:	DIRVGDIIRV KSEEPIPADT IILSSSEPEG LCYIETANLD GETNLKIKQS RVETAKFIDV 
361:	KTLKNMNGKV VSEQPNSSLY TYEGTMTLND RQIPLSPDQM ILRGATLRNT AWIFGLVIFT 
421:	GHETKLLRNA TATPIKRTAV EKIINRQIIR LFTVLIVLIL ISSIGNVIMS TADAKHLSYL 
481:	YLEGTNKAGL FFKDFLTFWI LFSNLVPISL FVTVELIKYY QAFMIGSDLD LYYEKTDTPT 
541:	VVRTSSLVEE LGQIEYIFSD KTGTLTRNIM EFKSCSIAGH CYIDKIPEDK TATVEDGIEV 
601:	GYRKFDDLKK KLNDPSDEDS PIINDFLTLL ATCHTVIPEF QSDGSIKYQA ASPDEGALVQ 
661:	GGADLGYKFI IRKGNSVTVL LEETGEEKEY QLLNICEFNS TRKRMSAIFR FPDGSIKLFC 
721:	KGADTVILER LDDEANQYVE ATMRHLEDYA SEGLRTLCLA MRDISEGEYE EWNSIYNEAA 
781:	TTLDNRAEKL DEAANLIEKN LILIGATAIE DKLQDGVPET IHTLQEAGIK IWVLTGDRQE 
841:	TAINIGMSCR LLSEDMNLLI INEETRDDTE RNLLEKINAL NEHQLSTHDM KSLALVIDGK 
901:	SLGFALEPEL EDYLLTVAKL CKAVICCRVS PLQKALVVKM VKRKSSSLLL AIASGANDVS 
961:	MIQAAHVGVG ISGMEGMQAA RSADIALGQF KFLKKLLLVH GSWSYQRISV AILYSFYKNT 
1021:	ALYMTQFWYV FANAFSGQSI MESWTMSFYN LFFTVWPPFV IGVFDQFVSS RLLERYPQLY 
1081:	KLGQKGQFFS VYIFWGWIIN GFFHSAIVFI GTILIYRYGF ALNMHGELAD HWSWGVTVYT 
1141:	TSVIIVLGKA ALVTNQWTKF TLIAIPGSLL FWLIFFPIYA SIFPHANISR EYYGVVKHTY 
1201:	GSGVFWLTLI VLPIFALVRD FLWKYYKRMY EPETYHVIQE MQKYNISDSR PHVQQFQNAI 
1261:	RKVRQVQRMK KQRGFAFSQA EEGGQEKIVR MYDTTQKRGK YGELQDASAN PFNDNNGLGS 
1321:	NDFESAEPFI ENPFADGNQN SNRFSSSRDD ISFDI