Structural Insights into Separase Architecture and Substrate Recognition through Computational Modelling of Caspase-Like and Death Domains
Abstract
Separases are large proteins that mediate sister chromatid disjunction in all eukaryotes. They belong to clan CD of cysteine peptidases and contain a well-conserved C-terminal catalytic protease domain similar to caspases and gingipains. However, unlike other well-characterized groups of clan CD peptidases, there are no high-resolution structures of separases and the details of their regulation and substrate recognition are poorly understood. Here we undertook an in-depth bioinformatical analysis of separases from different species with respect to their similarity in amino acid sequence and protein fold in comparison to caspases, MALT-1 proteins (mucosa-associated lymphoidtissue lymphoma translocation protein 1) and gingipain-R. A comparative model of the single C-terminal caspase-like domain in separase from C. elegans suggests similar binding modes of substrate peptides between these protein subfamilies, and enables differences in substrate specificity of separase proteins to be rationalised. We also modelled a newly identified putative death domain, located N-terminal to the caspase-like domain. The surface features of this domain identify potential sites of protein-protein interactions. Notably, we identified a novel conserved region with the consensus sequence WWxxRxxLD predicted to be exposed on the surface of the death domain, which we termed the WR motif. We envisage that findings from our study willmore »
- Authors:
-
- Univ. of Leicester (United Kingdom)
- Wake Forest Univ., Winston-Salem, NC (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- Cancer Research UK
- OSTI Identifier:
- 1233331
- Grant/Contract Number:
- C24461/A12772
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS Computational Biology (Online)
- Additional Journal Information:
- Journal Name: PLoS Computational Biology (Online); Journal Volume: 11; Journal Issue: 10; Journal ID: ISSN 1553-7358
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; sequence alignment; Caenorhabditis elegans; sequence and motif analysis; multiple alignment calculation; protein structure comparison; proteases; protein structure prediction; Saccharomyces cerevisiae
Citation Formats
Winter, Anja, Schmid, Ralf, Bayliss, Richard, and Fetrow, Jacquelyn S. Structural Insights into Separase Architecture and Substrate Recognition through Computational Modelling of Caspase-Like and Death Domains. United States: N. p., 2015.
Web. doi:10.1371/journal.pcbi.1004548.
Winter, Anja, Schmid, Ralf, Bayliss, Richard, & Fetrow, Jacquelyn S. Structural Insights into Separase Architecture and Substrate Recognition through Computational Modelling of Caspase-Like and Death Domains. United States. https://doi.org/10.1371/journal.pcbi.1004548
Winter, Anja, Schmid, Ralf, Bayliss, Richard, and Fetrow, Jacquelyn S. Thu .
"Structural Insights into Separase Architecture and Substrate Recognition through Computational Modelling of Caspase-Like and Death Domains". United States. https://doi.org/10.1371/journal.pcbi.1004548. https://www.osti.gov/servlets/purl/1233331.
@article{osti_1233331,
title = {Structural Insights into Separase Architecture and Substrate Recognition through Computational Modelling of Caspase-Like and Death Domains},
author = {Winter, Anja and Schmid, Ralf and Bayliss, Richard and Fetrow, Jacquelyn S.},
abstractNote = {Separases are large proteins that mediate sister chromatid disjunction in all eukaryotes. They belong to clan CD of cysteine peptidases and contain a well-conserved C-terminal catalytic protease domain similar to caspases and gingipains. However, unlike other well-characterized groups of clan CD peptidases, there are no high-resolution structures of separases and the details of their regulation and substrate recognition are poorly understood. Here we undertook an in-depth bioinformatical analysis of separases from different species with respect to their similarity in amino acid sequence and protein fold in comparison to caspases, MALT-1 proteins (mucosa-associated lymphoidtissue lymphoma translocation protein 1) and gingipain-R. A comparative model of the single C-terminal caspase-like domain in separase from C. elegans suggests similar binding modes of substrate peptides between these protein subfamilies, and enables differences in substrate specificity of separase proteins to be rationalised. We also modelled a newly identified putative death domain, located N-terminal to the caspase-like domain. The surface features of this domain identify potential sites of protein-protein interactions. Notably, we identified a novel conserved region with the consensus sequence WWxxRxxLD predicted to be exposed on the surface of the death domain, which we termed the WR motif. We envisage that findings from our study will guide structural and functional studies of this important protein family.},
doi = {10.1371/journal.pcbi.1004548},
journal = {PLoS Computational Biology (Online)},
number = 10,
volume = 11,
place = {United States},
year = {Thu Oct 29 00:00:00 EDT 2015},
month = {Thu Oct 29 00:00:00 EDT 2015}
}
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