The Crystal Structure of DJ-1, a Protein Related to Male Fertility and Parkinson's Disease

Honbou, Kazuya; Suzuki, Nobuo; Horiuchi, Masataka; Niki, Takeshi; Taira, Takahiro; Ariga, Hiroyoshi; Inagaki, Fuyuhiko

doi:10.1074/jbc.m305878200

Cited by 213 publications

(228 citation statements)

References 29 publications

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“…Thus, in this scenario it is intriguing to know what could be the function of MYCBP, a protein that has been described to stimulate the activation of Ebox-dependent transcription of C-myc proto-oncogene [35]. The same can be argued for the product of the PARK7 gene encoding an RNA-binding regulatory subunit of oncogene DJ1 [36]. The notion that perhaps the spermatozoon delivers something more than just the genomic DNA to the oocyte started to change with the identification of RNAs that are also transferred to the ova [37].…”

Section: Resultsmentioning

confidence: 99%

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Proteomic identification of human sperm proteins

Martínez-Heredia¹,

Estanyol²,

Ballescà³

et al. 2006

Proteomics

233

177

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Conventional 1-DE has in the past provided a wealth of information concerning the major sperm proteins. However, so far there are relatively few reports exploiting the potential of the present proteomic tools to identify and to study additional yet-unidentified important proteins present in human spermatozoa. In the present work, 2-DE of proteins extracted from human normozoospermic spermatozoa led to the resolution of over 1000 spots. Subsequent excision from the gels of 145 spots and MALDI-TOF MS analysis allowed the identification of 98 different proteins. The function of these proteins turned out to be energy production (23%), transcription, protein synthesis, transport, folding and turnover (23%), cell cycle, apoptosis and oxidative stress (10%), signal transduction (8%), cytoskeleton, flagella and cell movement (10%), cell recognition (7%), metabolism (6%) and unknown function (11%). As many as 23% of the proteins identified have not been previously described as being expressed in human spermatozoa. The present data provide an important clue towards determining the function of these proteins and opens up the possibility to perform additional experiments.

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Section: Resultsmentioning

confidence: 99%

“…Another interesting protein that could have been included in this category is the product of PARK7, which we have included under the protein synthesis category (see above). This protein many also function as a redox-sensitive chaperone and as a sensor for oxidative stress, and has been related to male fertility and Parkinson's disease [36].…”

mentioning

confidence: 99%

Proteomic identification of human sperm proteins

Martínez-Heredia¹,

Estanyol²,

Ballescà³

et al. 2006

Proteomics

233

177

View full text Add to dashboard Cite

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“…The crystal structure of DJ-1 reveals a high degree of structural similarity between DJ-1 and the bacterial protease PH1704 and E. coli chaperone protein Hsp31 (25)(26)(27)(28)(29). However, unlike PH1704 and Hsp31, DJ-1 does not have a Cys-His-(Glu/Asp) catalytic triad.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the sequence and structural homology of DJ-1 with the PfpI family of intracellular proteases, it has been proposed that Cys-106 of DJ-1 may serve as the active site nucleophile for its catalytic function (25,26,28). To examine this possibility, we assessed the effect of mutation of Cys-106 to an Ala (C106A) on the protease activity of DJ-1.…”

Section: Dj-1 Functions As a Cysteinementioning

confidence: 99%

“…We and other groups have recently solved the crystal structure of human DJ-1, which shows that DJ-1 adopts a helix-strand-helix sandwich structure similar to the bacterial protease PH1704 and Escherichia coli chaperone protein Hsp31 (25)(26)(27)(28)(29). However, it is unclear whether DJ-1 has a protease or chaperone function because the Cys-His-(Glu/Asp) catalytic triad and the quaternary structure of PH1704 and Hsp31 are not conserved in DJ-1.…”

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confidence: 99%

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Familial Parkinson's Disease-associated L166P Mutation Disrupts DJ-1 Protein Folding and Function

Olzmann

Brown

Wilkinson

et al. 2004

Journal of Biological Chemistry

262

282

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Mutations in DJ-1, a protein of unknown function, were recently identified as the cause for an autosomal recessive, early onset form of familial Parkinson's disease. Here we report that DJ-1 is a dimeric protein that exhibits protease activity but no chaperone activity. The protease activity was abolished by mutation of Cys-106 to Ala, suggesting that DJ-1 functions as a cysteine protease. Our studies revealed that the Parkinson's disease-linked L166P mutation impaired the intrinsic folding propensity of DJ-1 protein, resulting in a spontaneously unfolded structure that was incapable of forming a homodimer with itself or a heterodimer with wild-type DJ-1. Correlating with the disruption of DJ-1 structure, the L166P mutation abolished the catalytic function of DJ-1. Furthermore, as a result of protein misfolding, the L166P mutant DJ-1 was selectively polyubiquitinated and rapidly degraded by the proteasome. Together these findings provide insights into the molecular mechanism by which loss-of-function mutations in DJ-1 lead to Parkinson's disease.

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Genetics of Parkinson's disease: What do mutations in DJ‐1 tell us?

Moore

Dawson

2003

Annals of Neurology

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's disease (PD), the second most common progressive neurodegenerative disorder, is characterized pathologically by the selective loss of dopaminergic neurons from the substantia nigra pars compacta and the presence of intracytoplasmic proteinaceous inclusions termed Lewy bodies 1,2 . The etiology of PD remains unclear, and although PD occurs most commonly as a sporadic idiopathic form, the recent identification of genetic mutations in rare familial cases of PD has provided tremendous insight into the molecular pathogenesis of this neurological disease. So far, three genes have been clearly linked to PD; ␣-synuclein, parkin and more recently DJ-1. A mutation in a fourth gene, UCH-L1, has also been implicated. 2-5The recent discovery of deletions or mutations in the DJ-1 gene will undoubtedly provide new clues to the pathogenesis of PD and open up new exciting areas of PD research. 6 While mutations in ␣-synuclein (and UCH-L1) result in a rare autosomal dominant form of PD, 2-4 mutations in DJ-1, like those of parkin, cause a clinically characteristic autosomal recessive juvenile onset form of PD (AR-JP).6 Thus, such mutations are thought to lead to a loss of DJ-1 function. While parkin mutations appear to be the most common cause of AR-JP accounting for up to half of all cases, 7 mutations in DJ-1 have so far only been detected in two consanguineous European families. The DJ-1 gene contains 8 exons; exons 1 A/B are alternatively spliced and non-coding, while exons 2 to 7 comprise the open reading frame (ORF) encoding a 189 amino acid protein. In one Dutch family, a large homozygous genomic deletion encompassing exons 1 A/B to 5 of DJ-1 leads to an absence of gene product, while in an Italian family a homozygous point mutation results in the substitution of a highly conserved leucine for a proline at position 166 (L166P) of the DJ-1 protein. 6 The L166P mutation, centrally located within a carboxyl-terminal ␣-helix, is predicted to disrupt the tertiary structure of the DJ-1 protein. Indeed, the recent elucidation of the crystal structure of DJ-1 demonstrates that DJ-1 exists in a homodimeric form, whereas the L166P mutant form appears to exist only as a monomer. [8][9][10] Hence, the pathogenic L166P mutation appears to impair dimerization of DJ-1, which is probably critical for its function. Our results confirm that the L166P mutation disrupts dimerization of DJ-1 through destabilization of the protein (D.J.M., L. Zhang, T.M.D and V.L.D.). Furthermore, while DJ-1 exhibits a ubiquitous cellular localization pattern, the L166P mutation results in mislocalization of DJ-1 to mitochondria. 6 Thus, in light of the fact that the functional role of DJ-1 remains elusive, investigating the effects of such mutations on the basic properties of DJ-1 can provide novel insights into how loss of DJ-1 function might lead to neurodegeneration. However, the elucidation of additional disease-causing DJ-1 mutations in AR-JP or sporadic PD patients will help to determine which critical properties of DJ-1 function are affected in PD suc...

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The Crystal Structure of DJ-1, a Protein Related to Male Fertility and Parkinson's Disease

Cited by 213 publications

References 29 publications

Proteomic identification of human sperm proteins

Proteomic identification of human sperm proteins

Familial Parkinson's Disease-associated L166P Mutation Disrupts DJ-1 Protein Folding and Function

Genetics of Parkinson's disease: What do mutations in DJ‐1 tell us?

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