User:Luana Ramos/YAP1

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Function

Yap1 is a transcription factor involved in oxidative stress response and redox homeostasis. It 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.^[3] 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 regulates the expression of up to 70 genes ^{[4] [5]}. 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 ^[6]. When overexpressed, YAP1 confers pleiotropic drug-resistance and increases cellular tolerance to cadmium, iron chelators and zinc.

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.

Structural highlights

Structure

In the active oxidized form, a nuclear export signal (NES) in the carboxy-terminal cysteine-rich domain is masked by disulphide-bond-mediated interactions with a conserved amino-terminal a-helix. Point mutations that weaken the hydrophobic interactions between the N-terminal a-helix and the C-terminal NES-containing domain abolished redox-regulated changes in subcellular localization of Yap1. Upon reduction of the disulphide bonds, Yap1 undergoes a change to an unstructured conformation that exposes the NES and allows redistribution to the cytoplasm. These results reveal the structural basis of redox-dependent Yap1 localization and provide a previously unknown mechanism of transcription factor regulation by reversible intramolecular disulphide bond formation. The oxidized form of Yap1 contains a protease-resistant domain, Yap1-RD, comprised of residues Asn279 to Arg313 of the n-CRD and Asn565 to Asn650 of the c-CRD, covalently attached via Cys303–Cys598 and Cys310–Cys629 disulphide bonds Previous experiments have shown that Leu619 is critically important for Yap1 nuclear export, whereas residues Ile614, Val616 and Leu623 are moderately important4,8.

our observations suggest that in reduced Yap1 the NES is exposed, allowing Yap1 to be exported from the nucleus by Crm1. Upon oxidation, Yap1 adopts a conformation in which the NES is concealed, as indicated in this structure, allowing Yap1 to accumulate in the nucleus.

To our knowledge, the oxidized Yap1-RD structure is the first known high resolution structure of the sensory domain of a eukaryotic transcription factor that is reversibly regulated by disulphide bond formation.^[5]

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 ^[7]. 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.^{[8] [5]}