Dataset Information

Isoform-specific intermolecular disulfide bond formation of heterochromatin protein 1 (HP1).

ABSTRACT: Three mammalian isoforms of heterochromatin protein 1 (HP1), ?, ?, and ?, play diverse roles in gene regulation. Despite their structural similarity, the diverse functions of these isoforms imply that they are additionally regulated by post-translational modifications. Here, we have identified intermolecular disulfide bond formation of HP1 cysteines in an isoform-specific manner. Cysteine 133 in HP1? and cysteine 177 in HP1? were involved in intermolecular homodimerization. Although both HP1? and HP1? contain reactive cysteine residues, only HP1? readily and reversibly formed disulfide homodimers under oxidative conditions. Oxidatively dimerized HP1? strongly and transiently interacted with TIF1?, a universal transcriptional co-repressor. Under oxidative conditions, HP1? dimerized and held TIF1? in a chromatin component and inhibited its repression ability. Our results highlight a novel, isoform-specific role for HP1 as a sensor of the cellular redox state.

SUBMITTER: Higo S

PROVIDER: S-EPMC2951208 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Isoform-specific intermolecular disulfide bond formation of heterochromatin protein 1 (HP1).

Higo Shuichiro S Asano Yoshihiro Y Kato Hisakazu H Yamazaki Satoru S Nakano Atsushi A Tsukamoto Osamu O Seguchi Osamu O Asai Mitsutoshi M Asakura Masanori M Asanuma Hiroshi H Sanada Shoji S Minamino Tetsuo T Komuro Issei I Kitakaze Masafumi M Takashima Seiji S

The Journal of biological chemistry 20100801 41

Three mammalian isoforms of heterochromatin protein 1 (HP1), α, β, and γ, play diverse roles in gene regulation. Despite their structural similarity, the diverse functions of these isoforms imply that they are additionally regulated by post-translational modifications. Here, we have identified intermolecular disulfide bond formation of HP1 cysteines in an isoform-specific manner. Cysteine 133 in HP1α and cysteine 177 in HP1γ were involved in intermolecular homodimerization. Although both HP1α an ...[more]

PMID: 20675861

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Project description:The protein secretory pathway must maintain homoeostasis while producing a wide assortment of proteins in different conditions. It is also used extensively to produce many useful proteins in biotechnology. As such, secretory pathway dysfunction can be highly detrimental to the cell, resulting in the molecular basis for many human diseases, and can drastically inhibit product titers in biochemical production. Because the secretory pathway is a highly-integrated, multi-organelle system, dysfunction can happen at many levels and dissecting the root cause can be challenging. To better understand some of these dysfunctions, we measured multiple systems-level states of the cell (physiology, transcriptome, metabolism) while secreting a small protein (insulin precursor) or a large protein (?-amylase). This was carried out in the presence and absence of HAC1, a key transcription factor in maintaining secretory homeostasis. Clear trends in cellular stress were apparent across multiple data resulting from our perturbations. In particular, processes involving (1) degradation of protein / recycling amino acids, (2) overall transcription/translation repression, and (3) oxidative stress. Apparent runaway oxidative radical production was explained by a thermodynamic model that we put forward for disulfide formation in the endoplasmic reticulum. This model predicts that balancing the relative rates of protein folding and disulfide bond formation are key to easing oxidative stress. These predictions have direct implications in how to engineer a broad range of recombinant proteins for secretion and provide potential hypotheses for the root causes of several secretory-associated diseases. Yeast strains were constructed that produce and secrete (a) IP or (b) ?-amylase and were compared to yeast strains containing (c) an empty vector in both wild-type and HAC1 deletion backgrounds. These strains are named WN (WT with empty vector), WI (WT secreting IP), WA (WT secreting ?-amylase), dN (?hac1 with empty vector), dI (?hac1 secreting IP), and dA (?hac1 secreting ?-amylase). Strains were characterized in batch fermentation and samples were taken in mid-exponential phase. Triplicate fermentations were carried out for each strain.

Dataset Information

Isoform-specific intermolecular disulfide bond formation of heterochromatin protein 1 (HP1).

Publications

Isoform-specific intermolecular disulfide bond formation of heterochromatin protein 1 (HP1).

Similar Datasets

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