User:Luana Ramos/YAP1

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.^[1] The activity of the transcription factor is controlled through oxidation of specific cysteine residues leading to the modification of its subcellular location. Oxidative stress (as well as carbon stress) induces nuclear accumulation and as a result Yap1 acts by regulating the expression of up to 70 genes ^{[2] [3]}. Yap1 can be activated upon exposure to hydrogen peroxide or thiol-reactive chemicals resulting in different adaptive gene responses. Nuclear export is restored when disulfide bonds are reduced by thioredoxin (TRX2), whose expression is controlled by YAP1, by negative autoregulation ^[4].

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 ^[3].

Structural highlights

Structure

In the oxidized form of Yap1, a nuclear export signal (NES) in the carboxy-terminal cysteine-rich domain is concealed 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, allowing Yap1 to accumulate in the nucleus. The oxidized form contains a protease-resistant domain, Yap1, comprised of residues of the n-CRD and Asn565 to Asn650 of the c-CRD, covalently attached via Cys303–Cys598 and Cys310–Cys629 disulphide bonds. After the reduction of the disulphide bonds, Yap1 changes to an unstructured conformation that exposes the NES and allows Yap1 to be exported from the nucleus, by Crm1, to the cytoplasm. Therefore the redox-dependent Yap1 localization is determined by a reversible intramolecular disulphide bond formation. The oxidized Yap1 structure is the first described high resolution structure of a eukaryotic transcription factor that is reversibly regulated by disulphide bond formation.^[3]

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 ^[5]. 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 (causing nuclear localization of YAP1), and the possibly stabilizing bond between (required for full activity of YAP1).

Domains

Yap1 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.^{[6] [3]}