Dataset Information

PSI-2: structural genomics to cover protein domain family space.

ABSTRACT: One major objective of structural genomics efforts, including the NIH-funded Protein Structure Initiative (PSI), has been to increase the structural coverage of protein sequence space. Here, we present the target selection strategy used during the second phase of PSI (PSI-2). This strategy, jointly devised by the bioinformatics groups associated with the PSI-2 large-scale production centers, targets representatives from large, structurally uncharacterized protein domain families, and from structurally uncharacterized subfamilies in very large and diverse families with incomplete structural coverage. These very large families are extremely diverse both structurally and functionally, and are highly overrepresented in known proteomes. On the basis of several metrics, we then discuss to what extent PSI-2, during its first 3 years, has increased the structural coverage of genomes, and contributed structural and functional novelty. Together, the results presented here suggest that PSI-2 is successfully meeting its objectives and provides useful insights into structural and functional space.

SUBMITTER: Dessailly BH

PROVIDER: S-EPMC2920419 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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PSI-2: structural genomics to cover protein domain family space.

Dessailly Benoît H BH Nair Rajesh R Jaroszewski Lukasz L Fajardo J Eduardo JE Kouranov Andrei A Lee David D Fiser Andras A Godzik Adam A Rost Burkhard B Orengo Christine C

Structure (London, England : 1993) 20090601 6

One major objective of structural genomics efforts, including the NIH-funded Protein Structure Initiative (PSI), has been to increase the structural coverage of protein sequence space. Here, we present the target selection strategy used during the second phase of PSI (PSI-2). This strategy, jointly devised by the bioinformatics groups associated with the PSI-2 large-scale production centers, targets representatives from large, structurally uncharacterized protein domain families, and from struct ...[more]

PMID: 19523904

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Project description:Simple Summary DnaJB6 is a human cellular protein quality control factor that prevents diverse peptides from forming disease-associated amyloid, a highly ordered fibrous protein aggregate. DnaJB6 protects human cells, animals and yeast from toxicity caused by amyloids composed of Huntington’s-related polyglutamine, Parkinson’s-related α-synuclein, and ALS- associated TDP-43, and it cures yeast of endogenous prions (infectious amyloids). However, structurally different amyloids of one and the same prion protein, and prions composed of them, can be insensitive to anti-amyloid activity of DnaJB6. This limitation raises concerns about developing DnaJB6 as a therapeutic for amyloid diseases. Prions showing this insensitivity are highly toxic to yeast with reduced function of Sis1, a yeast protein related to DnaJB6. To begin assessing how DnaJB6 might act on amyloid in cells we tested if DnaJB6 could protect yeast from this toxicity. Although it does not eliminate the prion, it protects cells from prion toxicity, but differently than Sis1. Our work provides insight into how human DnaJB6 counteracts cellular toxicity caused by amyloid and establishes an in vivo genetic system useful for studying DnaJB6-amyloid interactions to decipher its mechanisms of action. Abstract Human J-domain protein (JDP) DnaJB6 has a broad and potent activity that prevents formation of amyloid by polypeptides such as polyglutamine, A-beta, and alpha-synuclein, related to Huntington’s, Alzheimer’s, and Parkinson’s diseases, respectively. In yeast, amyloid-based [PSI+] prions, which rely on the related JDP Sis1 for replication, have a latent toxicity that is exposed by reducing Sis1 function. Anti-amyloid activity of DnaJB6 is very effective against weak [PSI+] prions and the Sup35 amyloid that composes them, but ineffective against strong [PSI+] prions composed of structurally different amyloid of the same Sup35. This difference reveals limitations of DnaJB6 that have implications regarding its therapeutic use for amyloid disease. Here, we find that when Sis1 function is reduced, DnaJB6 represses toxicity of strong [PSI+] prions and inhibits their propagation. Both Sis1 and DnaJB6, which are regulators of protein chaperone Hsp70, counteract the toxicity by reducing excessive incorporation of the essential Sup35 into prion aggregates. However, while Sis1 apparently requires interaction with Hsp70 to detoxify [PSI+], DnaJB6 counteracts prion toxicity by a different, Hsp70-independent mechanism.

Dataset Information

PSI-2: structural genomics to cover protein domain family space.

Publications

PSI-2: structural genomics to cover protein domain family space.

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