Mmd1p, a Novel, Conserved Protein Essential for Normal Mitochondrial Morphology and Distribution in the Fission Yeast<i>Schizosaccharomyces pombe</i>

Weir, Barbara A.; Yaffe, Michael P.

doi:10.1091/mbc.e03-06-0371

Cited by 47 publications

(38 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, DOHH seems to be functionally more significant in the fission yeast, S. pombe. The S. pombe homolog of the DOHH gene, Mmd1, was recently reported to be important for normal mitochondrial morphology and distribution in S. pombe (39). An mmd1 mutation (E66K) caused temperature-sensitive growth and defects in mitochondrial morphology and distribution at nonpermissive temperature.…”

Section: Discussionmentioning

confidence: 99%

Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: A HEAT-repeat-containing metalloenzyme

Park

Aravind²,

Wolff³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

138

159

View full text Add to dashboard Cite

The eukaryotic initiation factor 5A (eIF5A), a factor essential for eukaryotic cell proliferation, is the only cellular protein containing the polyamine-derived amino acid hypusine [N -(4-amino-2-hydroxybutyl)lysine]. Hypusine is formed in a posttranslational modification that involves two sequential enzymatic steps catalyzed by deoxyhypusine synthase and deoxyhypusine hydroxylase (DOHH). By screening a Saccharomyces cerevisiae GST-ORF library for expression of DOHH activity, we have cloned YJR070C as the gene encoding DOHH and identified the human homolog DOHH gene, HLRC1. Purified recombinant yeast and human DOHH enzymes effectively catalyzed hydroxylation of the deoxyhypusine residue in the eIF5A intermediate. Overexpression of human DOHH along with eIF5A precursor and deoxyhypusine synthase was required for overproduction of mature, hypusine-containing eIF5A in 293T and other mammalian cells. The Saccharomyces cerevisiae strain with deletion of YJR070C contained only deoxyhypusine but no hypusine, indicating that YJR070C was the single DOHH gene in this organism. One highly conserved DOHH homolog gene is found in a variety of eukaryotes from yeast to human. Sequence and structural analyses reveal that DOHH belongs to a family of HEAT-repeat-containing proteins, consisting of eight tandem repeats of an ␣-helical pair (HEAT motif) organized in a symmetrical dyad. The predicted structure is unrelated to the double-stranded ␤-helix type structures of the Fe(II)-and 2-oxoacid-dependent dioxygenases, such as collagen prolyl or lysyl hydroxylases. However, metal coordination sites composed of four strictly conserved histidine-glutamate sequences were identified, suggesting that DOHH enzymes have convergently evolved an iron-dependent hydroxylation mechanism. eukaryotic initiation factor 5A ͉ hypusine ͉ YJR070C

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: A HEAT-repeat-containing metalloenzyme

Park

Aravind²,

Wolff³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

138

159

View full text Add to dashboard Cite

show abstract

“…From gene disruption studies in S. cerevisiae (35)(36)(37)(38), it is well established that eIF5A and deoxyhypusine synthase are essential for eukaryotic cell viability and proliferation. Whereas DOHH is not essential in S. cerevisiae (5,15) or Schizosaccharomyces pombe (39), inactivation of the DOHH gene is recessively lethal in multicellular eukaryotes, e.g. Caenorhabditis elegans (40) and Drosophila melanogaster (41), suggesting a requirement for a fully modified eIF5A in higher eukaryotes.…”

Section: Discussionmentioning

confidence: 99%

Specificity of the Deoxyhypusine Hydroxylase-Eukaryotic Translation Initiation Factor (eIF5A) Interaction

Kang¹,

Kim²,

Wolff

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Deoxyhypusine hydroxylase (DOHH) is a novel metalloenzyme that catalyzes the final step of the post-translational synthesis of hypusine (N ⑀ -(4-amino-2-hydroxybutyl)lysine) in the eukaryotic translation initiation factor 5A (eIF5A). Hypusine synthesis is unique in that it occurs in only one protein, denoting the strict specificity of the modification enzymes toward the substrate protein. The specificity of the interaction between eIF5A and DOHH was investigated using human eIF5A (eIF5A-1 isoform) and human recombinant DOHH. DOHH displayed a strong preference for binding the deoxyhypusine-containing form of eIF5A, over the eIF5A precursor or the hypusine-containing eIF5A, indicating a role for the deoxyhypusine residue in binding. In addition to the deoxyhypusine residue, a large portion of the eIF5A polypeptide (>20 -90 amino acids) is required for effective modification by DOHH. We have identified the amino acid residues of DOHH that are critical for substrate binding by alanine substitution of 36 conserved amino acid residues. Of these, alanine substitution at Glu 57 is an unusual amino acid that occurs in all eukaryotes. It is formed posttranslationally in eukaryotic translation initiation factor 5A (eIF5A) 4 through the action of two enzymes (for a recent review, see Ref. 1). The first enzyme, deoxyhypusine synthase (DHS), catalyzes the NAD-dependent cleavage of spermidine and transfer of its 4-aminobutyl moiety to the ⑀-amino group of a specific lysine residue to form the deoxyhypusine (N ⑀ -(4-aminobutyl)lysine) residue (2, 3). The second enzyme, deoxyhypusine hydroxylase (DOHH), hydroxylates this intermediate to form the hypusine residue and mature eIF5A (4, 5).eIF5A and its modification enzymes, DHS and DOHH, are essential for mammalian cell proliferation (1, 6 -11). Various metal chelating inhibitors of DOHH, including mimosine and ciclopirox olamine, inhibit cell proliferation by causing cell cycle arrest at the G 1 /S boundary (12). Ciclolopirox olamine, in particular, exerted strong inhibition of human umbilical vein endothelial cell (HUVEC) proliferation and angiogenesis in model assays, suggesting the potential utility of DOHH inhibitors as antitumor agents (13). Although DOHH has been proposed as a potential target of antitumor therapy (13) and antihuman immunodeficiency virus type 1 therapy (14), no specific inhibitors of DOHH are currently available.The unique feature of hypusine formation is the strict substrate specificity of this protein modification. Hypusine synthesis occurs exclusively in one cellular protein, eIF5A precursor, at one specific lysine residue (Lys 50 for the human protein) and thereby represents one of the most specific protein modifications known to date. eIF5A and its modifying enzymes, DHS and DOHH, are highly conserved in all eukaryotes (1,8). The amino acid sequence conservation surrounding the hypusine site of eIF5A is especially high in eukaryotes, suggesting that the hypusine residue has an important basic function that has been preserved through evolution. Furthe...

show abstract

“…In fission yeast mitochondrial movement and distribution are mediated by the microtubule cytoskeleton, as is also observed in mammalian cells (16,43,46,47). Recent evidence has shown that mitochondria are an integral part of several signal transduction cascades involved in metabolism, cell cycle control, and differentiation (reviewed in references 6 and 29).…”

mentioning

confidence: 90%

Bot1p Is Required for Mitochondrial Translation, Respiratory Function, and Normal Cell Morphology in the Fission Yeast Schizosaccharomyces pombe

Wiley

Catanuto²,

Fontanesi

et al. 2008

Eukaryot Cell

View full text Add to dashboard Cite

Maintenance of cell morphology is essential for normal cell function. For eukaryotic cells, a growing body of recent evidence highlights a close interdependence between mitochondrial function, the cytoskeleton, and cell cycle control mechanisms; however, the molecular details of this interconnection are still not completely understood. We have identified a novel protein, Bot1p, in the fission yeast Schizosaccharomyces pombe. Mitochondria are energy-generating organelles that participate in multiple cell signaling cascades, which allow continuous communication with the rest of the cell. Recent studies underline the close relationship between mitochondria and cell morphology control, indicating that while mitochondrial movement, morphology, and function are regulated by the cytoskeleton in mostly uncharacterized ways, mitochondrial function is essential for both maintenance of normal morphology, particularly in neuronal cells, and for normal cell cycle progression (1, 29).The fission yeast Schizosaccharomyces pombe has been extensively used as a powerful genetic model organism for studying the molecular mechanisms of morphology and cell cycle control.

show abstract

Mmd1p, a Novel, Conserved Protein Essential for Normal Mitochondrial Morphology and Distribution in the Fission YeastSchizosaccharomyces pombe

Cited by 47 publications

References 28 publications

Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: A HEAT-repeat-containing metalloenzyme

Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: A HEAT-repeat-containing metalloenzyme

Specificity of the Deoxyhypusine Hydroxylase-Eukaryotic Translation Initiation Factor (eIF5A) Interaction

Bot1p Is Required for Mitochondrial Translation, Respiratory Function, and Normal Cell Morphology in the Fission Yeast Schizosaccharomyces pombe

Contact Info

Product

Resources

About