User:Luana Ramos/YAP1

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Structural highlights

Function

Transcription activator involved in oxidative stress response and redox homeostasis. Regulates the transcription of genes encoding antioxidant enzymes and components of the cellular thiol-reducing pathways, including the thioredoxin system (TRX2, TRR1), the glutaredoxin system (GSH1, GLR1), superoxide dismutase (SOD1, SOD2), glutathione peroxidase (GPX2), and thiol-specific peroxidases (TSA1, AHP1). The induction of some of these genes requires the cooperative action of both, YAP1 and SKN7. Preferentially binds to promoters with the core binding site 5'-TTA[CG]TAA-3'. Activity of the transcription factor is controlled through oxidation of specific cysteine residues resulting in the alteration of its subcellular location. Oxidative stress (as well as carbon stress, but not increased temperature, acidic pH, or ionic stress) induces nuclear accumulation and as a result YAP1 transcriptional activity. Activation by hydrogen peroxide or thiol-reactive chemicals elicit distinct adaptive gene responses. Nuclear export is restored when disulfide bonds are reduced by thioredoxin (TRX2), whose expression is controlled by YAP1, providing a mechanism for negative autoregulation. When overexpressed, YAP1 confers pleiotropic drug-resistance and increases cellular tolerance to cadmium, iron chelators and zinc.

Miscellaneous

One of 8 closely related fungi-specific YAP proteins (YAP1 to YAP8), which all seem to be transcription activators of the environmental stress response and metabolism control pathways and to have similar but not identical DNA binding specificities. Present with 1600 molecules/cell in log phase SD medium.

Relevance

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Subcellular Location

Oxidized YAP1 is found predominantly in the nucleus, while reduced YAP1 is continuously exported to the cytoplasm by CRM1/exportin 1. Nuclear import requires the karyopherin PSE1/KAP121 and is independent on YAP1 oxidation state.

Post-translational modification

Depending on the oxidative stress inducing agent, YAP1 can undergo two distinct conformational changes, both involving disulfide bond formation, and both masking the nuclear export signal, thus abolishing nuclear export by CRM1/exportin 1. The disulfide stress-inducing agent diamide leads to the formation of one of three possible disulfide bonds in the c-CRD. Peroxide stress induces the formation of the HYR1/GPX3- and YBP1-dependent interdomain disulfide bond between Cys-303 and Cys-598 (causing nuclear localization of YAP1), and the possibly stabilizing bond between Cys-310 and Cys-629 (required for full activity of YAP1).

Domains

Contains two cysteine rich domains (CRD), referred to as the N- and C-terminal CRD's, n-CRD (Cys-303, Cys-310 and Cys-315) and c-CRD (Cys-598, Cys-620 and Cys-629), respectively. Cys-315 is not conserved in orthologs in other yeast species. A nuclear export signal is embedded in the c-CRD, with which the nuclear export protein CRM1/exportin 1 interacts only in the absence of disulfide bonds (or otherwise oxidized cysteines) within the c-CRD or between the c-CRD and the n-CRD.