PDBsum entry 3ade

Transcription

PDB id

3ade

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Contents

			Protein chain

					289 a.a. *

			Ligands

					VAL-ASP-PRO-SER- THR-GLY-GLU-LEU


					SO4 ×9

			Waters ×37

* Residue conservation analysis

PDB id:

3ade

Links

Name:

Transcription

Title:

Crystal structure of keap1 in complex with sequestosome-1/p62

Structure:

Kelch-like ech-associated protein 1. Chain: a. Fragment: keap1-dc, unp residues 309-624. Synonym: cytosolic inhibitor of nrf2, inrf2. Engineered: yes. Sequestosome-1. Chain: b. Fragment: keap1 interacting region (kir), unp residues 346-359. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: inrf2, keap1, kiaa0132. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: sequestosome-1 peptide

Resolution:

2.80Å

R-factor:

0.178

R-free:

0.232

Authors:

H.Kurokawa,M.Yamamoto

Key ref:

M.Komatsu et al. (2010). The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol, 12, 213-223. PubMed id: 20173742

Date:

19-Jan-10

Release date:

16-Mar-10

PROCHECK

	Headers

	References

Protein chain

Q9Z2X8 (KEAP1_MOUSE) - Kelch-like ECH-associated protein 1 from Mus musculus

Seq: Struc:

Seq: Struc:					624 a.a. 289 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.?

[IntEnz] [ExPASy] [KEGG] [BRENDA]

	Nat Cell Biol 12:213-223 (2010)
PubMed id: 20173742

The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.
M.Komatsu, H.Kurokawa, S.Waguri, K.Taguchi, A.Kobayashi, Y.Ichimura, Y.S.Sou, I.Ueno, A.Sakamoto, K.I.Tong, M.Kim, Y.Nishito, S.Iemura, T.Natsume, T.Ueno, E.Kominami, H.Motohashi, K.Tanaka, M.Yamamoto.

ABSTRACT

Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21330634

A.A.Powolny, A.Bommareddy, E.R.Hahm, D.P.Normolle, J.H.Beumer, J.B.Nelson, and S.V.Singh (2011).
Chemopreventative potential of the cruciferous vegetable constituent phenethyl isothiocyanate in a mouse model of prostate cancer.

J Natl Cancer Inst, 103, 571-584.

21248839

B.Levine, N.Mizushima, and H.W.Virgin (2011).
Autophagy in immunity and inflammation.

Nature, 469, 323-335.

20812872

J.Lewerenz, and P.Maher (2011).
Control of redox state and redox signaling by neural antioxidant systems.

Antioxid Redox Signal, 14, 1449-1465.

21247355

J.Sastri, and E.M.Campbell (2011).
Recent Insights into the Mechanism and Consequences of TRIM5α Retroviral Restriction.

AIDS Res Hum Retroviruses, 27, 231-238.

21220332

K.Fujita, D.Maeda, Q.Xiao, and S.M.Srinivasula (2011).
Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation.

Proc Natl Acad Sci U S A, 108, 1427-1432.

21365312

L.Baird, and A.T.Dinkova-Kostova (2011).
The cytoprotective role of the Keap1-Nrf2 pathway.

Arch Toxicol, 85, 241-272.

20728362

R.Scherz-Shouval, and Z.Elazar (2011).
Regulation of autophagy by ROS: physiology and pathology.

Trends Biochem Sci, 36, 30-38.

21146253

S.Billmann-Born, S.Lipinski, J.Böck, A.Till, P.Rosenstiel, and S.Schreiber (2011).
The complex interplay of NOD-like receptors and the autophagy machinery in the pathophysiology of Crohn disease.

Eur J Cell Biol, 90, 593-602.

21369766

S.L.Slocum, and T.W.Kensler (2011).
Nrf2: control of sensitivity to carcinogens.

Arch Toxicol, 85, 273-284.

21295136

T.M.Stępkowski, and M.K.Kruszewski (2011).
Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis.

Free Radic Biol Med, 50, 1186-1195.

21349088

V.Deretic (2011).
Autophagy in immunity and cell-autonomous defense against intracellular microbes.

Immunol Rev, 240, 92.

21585316

V.O.Tkachev, E.B.Menshchikova, and N.K.Zenkov (2011).
Mechanism of the Nrf2/Keap1/ARE Signaling System.

Biochemistry (Mosc), 76, 407-422.

21392184

Y.Hirotsu, F.Katsuoka, K.Itoh, and M.Yamamoto (2011).
Nrf2 degron-fused reporter system: a new tool for specific evaluation of Nrf2 inducers.

Genes Cells, 16, 406-415.

21482715

Y.Inami, S.Waguri, A.Sakamoto, T.Kouno, K.Nakada, O.Hino, S.Watanabe, J.Ando, M.Iwadate, M.Yamamoto, M.S.Lee, K.Tanaka, and M.Komatsu (2011).
Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells.

J Cell Biol, 193, 275-284.

20842363

A.C.Ng (2010).
Integrative systems biology and networks in autophagy.

Semin Immunopathol, 32, 355-361.

20571384

A.Huett, G.Goel, and R.J.Xavier (2010).
A systems biology viewpoint on autophagy in health and disease.

Curr Opin Gastroenterol, 26, 302-309.

20421418

A.Lau, X.J.Wang, F.Zhao, N.F.Villeneuve, T.Wu, T.Jiang, Z.Sun, E.White, and D.D.Zhang (2010).
A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62.

Mol Cell Biol, 30, 3275-3285.

20577044

A.Till, and S.Subramani (2010).
A balancing act for autophagin.

J Clin Invest, 120, 2273-2276.

21041446

B.E.Riley, S.E.Kaiser, T.A.Shaler, A.C.Ng, T.Hara, M.S.Hipp, K.Lage, R.J.Xavier, K.Y.Ryu, K.Taguchi, M.Yamamoto, K.Tanaka, N.Mizushima, M.Komatsu, and R.R.Kopito (2010).
Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection.

J Cell Biol, 191, 537-552.

20965422

G.Kroemer, G.Mariño, and B.Levine (2010).
Autophagy and the integrated stress response.

Mol Cell, 40, 280-293.

20577052

G.Mariño, A.F.Fernández, S.Cabrera, Y.W.Lundberg, R.Cabanillas, F.Rodríguez, N.Salvador-Montoliu, J.A.Vega, A.Germanà, A.Fueyo, J.M.Freije, and C.López-Otín (2010).
Autophagy is essential for mouse sense of balance.

J Clin Invest, 120, 2331-2344.

20378532

I.M.Copple, A.Lister, A.D.Obeng, N.R.Kitteringham, R.E.Jenkins, R.Layfield, B.J.Foster, C.E.Goldring, and B.K.Park (2010).
Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway.

J Biol Chem, 285, 16782-16788.

20404090

K.Taguchi, J.M.Maher, T.Suzuki, Y.Kawatani, H.Motohashi, and M.Yamamoto (2010).
Genetic analysis of cytoprotective functions supported by graded expression of Keap1.

Mol Cell Biol, 30, 3016-3026.

21029296

K.Y.Hur, H.S.Jung, and M.S.Lee (2010).
Role of autophagy in β-cell function and mass.

Diabetes Obes Metab, 12, 20-26.

20534340

M.Kobayashi (2010).
Harnessing the antioxidant power with ARE-inducing compounds.

Chem Biol, 17, 419-420.

20670274

M.Komatsu, and Y.Ichimura (2010).
Selective autophagy regulates various cellular functions.

Genes Cells, 15, 923-933.

20616151

M.Y.Heng, D.K.Duong, R.L.Albin, S.J.Tallaksen-Greene, J.M.Hunter, M.J.Lesort, A.Osmand, H.L.Paulson, and P.J.Detloff (2010).
Early autophagic response in a novel knock-in model of Huntington disease.

Hum Mol Genet, 19, 3702-3720.

20811354

N.Mizushima, and B.Levine (2010).
Autophagy in mammalian development and differentiation.

Nat Cell Biol, 12, 823-830.

20190829

T.E.Rusten, and H.Stenmark (2010).
p62, an autophagy hero or culprit?

Nat Cell Biol, 12, 207-209.

20548099

T.Saitoh, and S.Akira (2010).
Regulation of innate immune responses by autophagy-related proteins.

J Cell Biol, 189, 925-935.

20446769

V.Calabrese, C.Cornelius, A.T.Dinkova-Kostova, E.J.Calabrese, and M.P.Mattson (2010).
Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders.

Antioxid Redox Signal, 13, 1763-1811.

20814791

Y.Ichimura, and M.Komatsu (2010).
Selective degradation of p62 by autophagy.

Semin Immunopathol, 32, 431-436.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.