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The Maltose Permease Encoded by the MAL61 Gene of Saccharomyces

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The Maltose Permease Encoded by the MAL61 Gene of Saccharomyces Copyright 0 1989 by the Genetics Society of America The Maltose Permease Encodedby the MAL61 Gene of Saccharomyces cerevisiae Exhibits Both Sequence and Structural Homology to Other Sugar Transporters Qi Cheng and Corinne A. Michels Department of Biology, Queens College and the Graduate School of the City Uniwersity of New York, Flushing, New York 11367 Manuscript received November2 1, 1988 Accepted for publication August 10, 1989 ABSTRACT The MAL61 gene of Saccharomyces cerewisiae encodes maltose permease,a protein required for the transport of maltose across the plasma membrane. Here we report the nucleotide sequence of the cloned MAL61 gene. A single 1842 bpopen reading frame is present within this region encodingthe 6 14 residue putative MAL61 protein. Hydropathy analysis suggests that the secondary structure consists of two blocks of six transmembrane domains separated by an approximately 71 residue intracellular region. The N-terminal and C-terminal domains of100 and 67 residues in length, respectively, also appear to be intracellular. Significant sequence and structural homology is seen between theMAL61 protein andthe Saccharomyces high-affinity glucose transporter encodedby the SNF3 gene, theKluyueromyces lactis lactose permease encoded by the LAC12 gene, the human HepG2 glucose transporter and the Escherichia coli xylose and arabinose transporters encodedby the xylE and araE genes, indicating that all are members of a family of sugar transporters andare related either functionally or evolutionarily. A mechanism for glucose-induced inactivation of maltose transport activity is discussed. ALTOSEfermentation in the Saccharomyces indication that the gene encoding maltose permease M yeasts is initiated by the transport of the disac- mapped to any of the MAL loci came from the iden- charide across the plasma membrane. This transport tification of a MALI-linked temperature-sensitive is carried out by maltose permease and the process is maltose transportmutation (GOLDENTHAL,COHEN the ratelimiting step in fermentation. An understand- and MARMUR1983). All of the MAL loci have been ing of the mechanisms controlling maltose transport cloned and structurally and functionallycompared is therefore fundamental to an understanding of the (FEDEROFFet al. 1982; NEEDLEMANand MICHELS factors regulating maltose fermentation. 1983; CHARRON,DUBIN and MICHELS1986; CHAR- The Saccharomyces maltose uptake system is an RON and MICHELS 1987; CHARRONet al. 1989). The inducibleactive transport system (HARRIS and MAL loci are all highly sequence-homologous, exhib- THOMPSON196 1; OKADAand HALVORSON1964; DE iting only a few restriction site polymorphisms. Each KROON and KONINGSBERGER1970; SERRANO1977). locus is a complex locus containing three genes re- SERRANO(1977) reports that this transport is inde- quired for maltose fermentation: GENEs 1, 2, and 3 pendent of intracellular ATP levels but is coupled to (NEEDLEMANet al. 1984). We have established a two the electrochemical gradient of protons. That is, malt- digit numbering system in order to distinguish the ose transport occurs via a proton symport system. As GENE 1, 2 or 3 functions mapping to the different has been seen in the glucose and galactose transport MAL loci. The first digit indicates the locus position systems of Saccharomyces, the maltose transport sys- and thesecond the GENE function (NEEDLEMANet al. tem exists in botha high and a low affinity form 1984; CHARRONand MICHELS1987, 1988). Thus, the (BISSON and FRAENKEL 1983a,b,1984; RAMOS, SZKUTNICKAand CIRILLO1989; BUSTURIAand LA- MAL61 gene is the GENE 1 function mapping to the MAL6 locus. GUNAS 1985). The basis of the differencebetween the two forms of these sugar transporters is not under- Transcription of GENEs 1 and 2 is induced by stood. maltose and repressed by glucose (NEEDLEMANet al. Saccharomyces strains ableto fermentmaltose carry 1984). That GENE 2 encodesmaltase is inferred from any one of five MAL loci: MALI, MAL2, MAL3, MAL4, the identification of an allele of the MAL12 gene (that and MAL6 (reviewed by BARNETT1976). The first is, GENE 2 of the MALI locus) that encodes a tem- perature-sensitive maltase (DUBINet al. 1985). GENE The publication costs of this article were partly defrayed by the payment of page charges. This article must therefore be hereby marked “advertisement” 1 encodes maltose permease. This conclusion is based in accordance with 18 U.S.C. $1734 solely to indicate this fact. on several lines of evidence reported by Y. S. CHANG, Genetics 123: 477-484 (November, 1989) 478 andQ. Cheng C. A. Michels R. A. DUBIN,E. PERKINS,C. A. MICHELSand R. B. lumbia University College of Physicians and Surgeons,New NEEDLEMAN (unpublishedresults). Point mutations in York; the profiles were made using the algorithmdeveloped by KYTE and DOOLITTLE(1 982) andutilized the values of the MAL61 gene as well as a deletion/disruption of EISENBERG(1 984)with a 2 1 -residuewindow. the MAL61 gene completely abolish maltose transport activity. Transformation of these mutant strains with RESULTS high copy plasmids carrying the MAL61 gene leads to up to a tenfold increase in maltose permease activity Sequence of the MAL61 gene and the proposed as compared to the single-copy parental strain. Most secondary structure of the deduced protein: Figure significantly, the integration of a fragment carrying 2 presents the sequence of the DNA fragment con- the yeast URA3 gene into the coding regionof MAL61 taining theMAL61 gene starting at theScaI site shown near the N-terminal end results in a low level consti- in Figure1 andextending to the right for 2000 tutive transcription of MAL61 and in a low level basepairs. A single large open reading frame is ob- constitutive synthesis of maltose permease. GENE 3 served with the AUG codonof the N-terminal methi- encodes the MAL activator and the product of this onine located 105 base pairs from the ScaI site. No gene is a cysteine-zinc finger protein (CHANG et al. other large open reading frames are observed in any 1988; KIM and MICHELS 1988; SOLLITIand MARMUR of the five other reading frames. The orientation of 1988). this single 1842 basepair open reading frame is con- This report presents the sequence of the MAL61 sistent with the size of the maltose inducible transcript gene. Analysis of the deduced aminoacid sequence of of the MAL61 gene (2.0 kbp) and with the direction the proposed MAL61 protein indicates that it is an of transcription of the MAL61 gene as reported in integralmembrane protein. Additionally, MAL61 NEEDLEMANet al. (1984). Construction of a MAL61- protein shows significant homology to several other lacz fusion at the EcoRI site near the N-terminal end sugar transport proteins fromyeast and other species. of the coding region supports the conclusion that the This homology is seen both on thelevel ofthe primary AUG codon indicated as the translation initiation can sequence and on thelevel of secondary structure. function as such in Saccharomyces (J. LEVINE,L. TANOUYEand C. A. MICHELS,unpublished results). A MATERIALSAND METHODS consensus “TATA” sequence is located at position -89 to -94. The sequence of the open reading frame Sequencing: Figure 1 shows a restriction endonuclease predicts a 67,174 dalton protein of 614 amino acid map of the MAL61 gene. Sequencing was done according to the method of SANGER,NICKLEN and COULSON(1977). residues. The region was divided into threefragments: the PstI-EcoRI Figure 2 also depicts the positions of twelve postu- fragment containing the MAL61 upstream sequences and lated hydrophobic transmembrane domains. Each of the 5’-end of thegene; the 1.7-kb EcoRI-Sal1 fragment the twelve postulated 2 1-residue transmembrane do- containing sequences internal to the MAL61 gene; and the mains has an average hydrophobicity value of greater SalI-Hind111 fragment containing the 3’-end of the gene. Each of these was then sequenced by acombination of than 0.42. As in the SNF3 protein,no signal sequence methods. Nested deletions within the MAL61-insert frag- is seen at the N-terminal end of the MAL61 protein ments were constructed with the fragment cloned into the and thefirst predicted transmembrane domainbegins M 13 sequencing vector mpl8 using exonuclease 111 and at residue 100, suggesting that the N-terminal 100 these were sequenced using the universal primer (MESSING amino acid residues lie on the cytoplasmic face of the 1983; HENIKOFF 1984).Gaps were filled by using oligonu- cleotide primers identical to known sequences. Nested dele- plasma membrane. The overall secondary structure tionswere also constructed using Ba131 todegrade the of the MAL61 protein thus appears to consist of two MAL61-insert fragment cloned in the plasmid vector blocks of six transmembrane domains separatedby an pBR325. For sequencing, these deletions were subcloned approximately 7 1 residue intracellular region. Both into the M 13 sequencing vectors. Sequencing of the second the 100 N-terminal residues and the 67 C-terminal strand was carried out using the 3.6-kb BglII-Hind111 frag- ment containing the entire MAL61 gene cloned into the residues are predicted to lie on the cytoplasmic face M13vector mp19.This was sequenced with a series of of the plasma membrane. Although two potential N- oligonucleotide primers complementary to known MAL61 linked glycosylation sites are foundat Asn-15 and sequence. Asn-27, these may notbe modified since they lie Computer analysis: Sequence data were analyzed using within the proposed cytoplasmic N-terminal region. the programs of IntelliGenetics, Inc. of Palo Alto, Califor- nia. Alignment of the MAL61 protein sequence with several This remains to be determinedsince it has been shown other transport proteinsequences was carried out using the that tunicamycin inhibits the synthesis of the maltose GENALIGN program. GENALIGN is a copyrighted soft- transport system inSaccharomyces (LAGUNAS,DEJUAN ware product of IntelliGenetics, Inc.; the program was de- and BENITO1986). Work is now in progress in our veloped by HUGOMARTINEZ of the University of California laboratory to test the predicted membrane topology at San Francisco. The hydropathy plots shown in Figure 4 comparing MAL61 and SNF3 proteins are thegift ofJOHN of the maltose permease.
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