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EMBO J. Jan 16, 1995; 14(2): 313–320.
PMCID: PMC398085

Heme binds to a short sequence that serves a regulatory function in diverse proteins.

Abstract

Heme is a prosthetic group for numerous enzymes, cytochromes and globins, and it binds tightly, sometimes covalently, to these proteins. Interestingly, heme also potentiates binding of the yeast transcriptional activator HAP1 to DNA and inhibits mitochondrial import of the mammalian delta-aminolevulinate synthase (ALAS) and the catalytic activity of the reticulocyte kinase, HRI. All three of these proteins contain a short sequence, the heme regulatory motif (HRM), that occurs six times adjacent to the HAP1 DNA binding domain, twice in the leader targeting sequence of ALAS and twice near the catalytic domain of the HRI kinase. Here we show that a 10 amino acid peptide containing the HRM consensus binds to heme in the micromolar range, and shifts the heme absorption spectrum to a longer wavelength, a direction opposite to the change caused by cytochromes or globins. Further, we show that a single HRM regulates the acidic activation domains of HAP1 and GAL4 independently of regulation of DNA binding of the transcription factors. These findings thus establish a novel heme binding sequence which is structurally distinct from sequences in globins or cytochromes and which has a regulatory function.

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  • Becker DM, Fikes JD, Guarente L. A cDNA encoding a human CCAAT-binding protein cloned by functional complementation in yeast. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1968–1972. [PMC free article] [PubMed]
  • Brent R, Ptashne M. A eukaryotic transcriptional activator bearing the DNA specificity of a prokaryotic repressor. Cell. 1985 Dec;43(3 Pt 2):729–736. [PubMed]
  • Chen JJ, Throop MS, Gehrke L, Kuo I, Pal JK, Brodsky M, London IM. Cloning of the cDNA of the heme-regulated eukaryotic initiation factor 2 alpha (eIF-2 alpha) kinase of rabbit reticulocytes: homology to yeast GCN2 protein kinase and human double-stranded-RNA-dependent eIF-2 alpha kinase. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7729–7733. [PMC free article] [PubMed]
  • Creusot F, Verdière J, Gaisne M, Slonimski PP. CYP1 (HAP1) regulator of oxygen-dependent gene expression in yeast. I. Overall organization of the protein sequence displays several novel structural domains. J Mol Biol. 1988 Nov 20;204(2):263–276. [PubMed]
  • Drygas ME, Lambowitz AM, Nargang FE. Cloning and analysis of the Neurospora crassa gene for cytochrome c heme lyase. J Biol Chem. 1989 Oct 25;264(30):17897–17906. [PubMed]
  • Dumont ME, Ernst JF, Hampsey DM, Sherman F. Identification and sequence of the gene encoding cytochrome c heme lyase in the yeast Saccharomyces cerevisiae. EMBO J. 1987 Jan;6(1):235–241. [PMC free article] [PubMed]
  • Eilers M, Schatz G. Binding of a specific ligand inhibits import of a purified precursor protein into mitochondria. Nature. 1986 Jul 17;322(6076):228–232. [PubMed]
  • Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. [PubMed]
  • Friden P, Schimmel P. LEU3 of Saccharomyces cerevisiae encodes a factor for control of RNA levels of a group of leucine-specific genes. Mol Cell Biol. 1987 Aug;7(8):2708–2717. [PMC free article] [PubMed]
  • Fytlovich S, Gervais M, Agrimonti C, Guiard B. Evidence for an interaction between the CYP1(HAP1) activator and a cellular factor during heme-dependent transcriptional regulation in the yeast Saccharomyces cerevisiae. EMBO J. 1993 Mar;12(3):1209–1218. [PMC free article] [PubMed]
  • Guarente L, Lalonde B, Gifford P, Alani E. Distinctly regulated tandem upstream activation sites mediate catabolite repression of the CYC1 gene of S. cerevisiae. Cell. 1984 Feb;36(2):503–511. [PubMed]
  • Muhich ML, Boothroyd JC. Synthesis of trypanosome hsp70 mRNA is resistant to disruption of trans-splicing by heat shock. J Biol Chem. 1989 May 5;264(13):7107–7110. [PubMed]
  • Henkel T, Zabel U, van Zee K, Müller JM, Fanning E, Baeuerle PA. Intramolecular masking of the nuclear location signal and dimerization domain in the precursor for the p50 NF-kappa B subunit. Cell. 1992 Mar 20;68(6):1121–1133. [PubMed]
  • Lathrop JT, Timko MP. Regulation by heme of mitochondrial protein transport through a conserved amino acid motif. Science. 1993 Jan 22;259(5094):522–525. [PubMed]
  • Ma J, Ptashne M. Deletion analysis of GAL4 defines two transcriptional activating segments. Cell. 1987 Mar 13;48(5):847–853. [PubMed]
  • O'Halloran TV, Frantz B, Shin MK, Ralston DM, Wright JG. The MerR heavy metal receptor mediates positive activation in a topologically novel transcription complex. Cell. 1989 Jan 13;56(1):119–129. [PubMed]
  • Padmanaban G, Venkateswar V, Rangarajan PN. Haem as a multifunctional regulator. Trends Biochem Sci. 1989 Dec;14(12):492–496. [PubMed]
  • Pfeifer K, Prezant T, Guarente L. Yeast HAP1 activator binds to two upstream activation sites of different sequence. Cell. 1987 Apr 10;49(1):19–27. [PubMed]
  • Pfeifer K, Kim KS, Kogan S, Guarente L. Functional dissection and sequence of yeast HAP1 activator. Cell. 1989 Jan 27;56(2):291–301. [PubMed]
  • Picard D, Salser SJ, Yamamoto KR. A movable and regulable inactivation function within the steroid binding domain of the glucocorticoid receptor. Cell. 1988 Sep 23;54(7):1073–1080. [PubMed]
  • Picard D, Khursheed B, Garabedian MJ, Fortin MG, Lindquist S, Yamamoto KR. Reduced levels of hsp90 compromise steroid receptor action in vivo. Nature. 1990 Nov 8;348(6297):166–168. [PubMed]
  • Piña B, Berger S, Marcus GA, Silverman N, Agapite J, Guarente L. ADA3: a gene, identified by resistance to GAL4-VP16, with properties similar to and different from those of ADA2. Mol Cell Biol. 1993 Oct;13(10):5981–5989. [PMC free article] [PubMed]
  • Robertson DE, Farid RS, Moser CC, Urbauer JL, Mulholland SE, Pidikiti R, Lear JD, Wand AJ, DeGrado WF, Dutton PL. Design and synthesis of multi-haem proteins. Nature. 1994 Mar 31;368(6470):425–432. [PubMed]
  • Rotenberg MO, Maines MD. Characterization of a cDNA-encoding rabbit brain heme oxygenase-2 and identification of a conserved domain among mammalian heme oxygenase isozymes: possible heme-binding site? Arch Biochem Biophys. 1991 Nov 1;290(2):336–344. [PubMed]
  • Sikorski RS, Hieter P. A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics. 1989 May;122(1):19–27. [PMC free article] [PubMed]
  • Sze JY, Woontner M, Jaehning JA, Kohlhaw GB. In vitro transcriptional activation by a metabolic intermediate: activation by Leu3 depends on alpha-isopropylmalate. Science. 1992 Nov 13;258(5085):1143–1145. [PubMed]
  • Triggs-Raine BL, Doble BW, Mulvey MR, Sorby PA, Loewen PC. Nucleotide sequence of katG, encoding catalase HPI of Escherichia coli. J Bacteriol. 1988 Sep;170(9):4415–4419. [PMC free article] [PubMed]
  • Yamamoto KR. Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet. 1985;19:209–252. [PubMed]
  • Zhang L, Guarente L. HAP1 is nuclear but is bound to a cellular factor in the absence of heme. J Biol Chem. 1994 May 20;269(20):14643–14647. [PubMed]

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