Unison: An Integrated Platform for Computational Biology Discovery

Hart, Reece K.; Mukhyala, Kiran

doi:10.1142/9789812836939_0038

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…The domain compositions of the 592 MMCPs were analyzed by querying the Unison (http://unison-db.org) (Hart and Mukhyala, 2009) database, which calculates the presence of domains from the Pfam (Finn et al, 2008) and Prosite (Hulo et al, 2006) databases, as well as from signal sequence and transmembrane prediction algorithms (see Supplemental Experimental Procedures). Proteins and domains were hierarchically clustered (Eisen et al, 1998) using the Pearson correlations of the numbers of each domain appearing in each protein (Table S1 and S2).…”

Section: Resultsmentioning

confidence: 99%

The STARD9/Kif16a Kinesin Associates with Mitotic Microtubules and Regulates Spindle Pole Assembly

Torres

Summers

Peterson³

et al. 2011

Cell

112

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SUMMARY During cell division cells form the microtubule-based mitotic spindle, a highly specialized and dynamic structure that mediates proper chromosome transmission to daughter cells. Cancer cells can show perturbed mitotic spindles and an approach in cancer treatment has been to trigger cell killing by targeting microtubule dynamics or spindle assembly. To identify and characterize proteins necessary for spindle assembly, and potential antimitotic targets, we performed a proteomic and genetic analysis of 592 mitotic microtubule co-purifying proteins (MMCPs). Screening for regulators that affect both mitosis and apoptosis, we report the identification and characterization of STARD9, a kinesin-3 family member, which localizes to centrosomes and stabilizes the pericentriolar material (PCM). STARD9-depleted cells have fragmented PCM, form multipolar spindles, activate the spindle assembly checkpoint (SAC), arrest in mitosis, and undergo apoptosis. Interestingly, STARD9-depletion synergizes with the chemotherapeutic agent taxol to increase mitotic death, demonstrating that STARD9 is a mitotic kinesin and a potential anti-mitotic target.

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Section: Resultsmentioning

confidence: 99%

The STARD9/Kif16a Kinesin Associates with Mitotic Microtubules and Regulates Spindle Pole Assembly

Torres

Summers

Peterson³

et al. 2011

Cell

112

View full text Add to dashboard Cite

show abstract

“…The Pfam domain boundaries of the coding sequences were retrieved from Unison (http://unison-db.org/), a precomputed database of protein annotations [Hart and Mukhyala, 2009]. Domains were predicted using Hmmsearch [Eddy, 1998] and an e-value cutoff of 0.001.…”

Section: Pfam Domain Identification and Multiple Sequence Alignmentmentioning

confidence: 99%

Inferring the functional effects of mutation through clusters of mutations in homologous proteins

Yue¹,

Forrest²,

Kaminker³

et al. 2010

Hum. Mutat.

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Inferring functional consequences is a bottleneck in high-throughput cancer mutation discovery and genetic association studies. Most polymorphisms and germline mutations are unlikely to have functionally significant consequences. Most cancer somatic mutations do not contribute to tumorigenesis and are not under selective pressure. Identifying and understanding functionally important mutations can clarify disease biology and lead to new therapeutic and diagnostic opportunities. We investigated the extent to which protein mutations with functional consequences are enriched in clusters at conserved positions across related proteins. We found that disease-causing mutations form clusters more than random mutations or single nucleotide polymorphisms, confirming that mutation hotspots occur at the domain level. In addition to helping to identify functionally significant mutations, analysis of clustered mutations can indicate the mechanism and consequences for protein function. Our analysis focused on somatic cancer mutations suggests functional impact for many, including singleton mutations in FGFR1, FGFR3, GFI1B, PIK3CG, RALB, RAP2B, and STK11. This provides evidence and generates mechanistic hypotheses for the contribution of such mutations to cancer. The same approach can be applied to mutations suspected of involvement in other diseases. An interactive Web application for browsing mutation clusters is available at http://www.mcluster.org.

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“…We took the full set of B-SIFT results for somatic mutations found in high-throughput cancer sequencing datasets and filtered based on alignment quality, B-SIFT score, and available expression information (see Methods ). The resulting mutations were then mapped to available protein structures (either exact structure or by homology) through queries to the Unison database [33] . A total of seventeen mutations could be mapped to a protein structure with a sequence identity of 50% or greater, which we then analyzed for their potential impact on protein function.…”

Section: Resultsmentioning

confidence: 99%

Bi-Directional SIFT Predicts a Subset of Activating Mutations

Lee¹,

Zhang²,

Mukhyala³

et al. 2009

PLoS ONE

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Advancements in sequencing technologies have empowered recent efforts to identify polymorphisms and mutations on a global scale. The large number of variations and mutations found in these projects requires high-throughput tools to identify those that are most likely to have an impact on function. Numerous computational tools exist for predicting which mutations are likely to be functional, but none that specifically attempt to identify mutations that result in hyperactivation or gain-of-function. Here we present a modified version of the SIFT (Sorting Intolerant from Tolerant) algorithm that utilizes protein sequence alignments with homologous sequences to identify functional mutations based on evolutionary fitness. We show that this bi-directional SIFT (B-SIFT) is capable of identifying experimentally verified activating mutants from multiple datasets. B-SIFT analysis of large-scale cancer genotyping data identified potential activating mutations, some of which we have provided detailed structural evidence to support. B-SIFT could prove to be a valuable tool for efforts in protein engineering as well as in identification of functional mutations in cancer.

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Unison: An Integrated Platform for Computational Biology Discovery

Cited by 3 publications

References 20 publications

The STARD9/Kif16a Kinesin Associates with Mitotic Microtubules and Regulates Spindle Pole Assembly

The STARD9/Kif16a Kinesin Associates with Mitotic Microtubules and Regulates Spindle Pole Assembly

Inferring the functional effects of mutation through clusters of mutations in homologous proteins

Bi-Directional SIFT Predicts a Subset of Activating Mutations

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