Chemical Ubiquitination for Decrypting a Cellular Code

Mathew Stanley, Satpal Virdee (Lead / Corresponding author)

Research output: Contribution to journalReview article

1 Citation (Scopus)
64 Downloads (Pure)

Abstract

The modification of proteins with ubiquitin (Ub) is an important regulator of eukaryotic biology and deleterious perturbation of this process is widely linked to the onset of various diseases. The regulatory capacity of the Ub signal is high and, in part, arises from the capability of Ub to be enzymatically polymerised to form polyubiquitin (polyUb) chains of 8 different linkage types. These distinct polyUb topologies can then be site-specifically conjugated to substrate proteins to elicit a number of cellular outcomes. Therefore, to further elucidate the biological significance of substrate ubiquitination, methodologies that allow the production of defined polyUb species and substrate proteins that are site-specifically modified with them are essential to progress our understanding. Many chemically inspired methods have recently emerged which fulfil many of the criteria necessary towards achieving deeper insight into Ub biology. With a view to providing immediate impact to traditional biology research labs, the aim of this review is to provide an overview of the techniques that are available for preparing Ub conjugates and polyUb chains with focus on approaches that use recombinant protein building blocks. These approaches either produce a native isopeptide, or analogue thereof, that can be hydrolyzable or non-hydrolyzable by deubiquitinases. The most significant biological insights that have already been garnered using such approaches will also be summarized.
Original languageEnglish
Pages (from-to)1297-1314
Number of pages18
JournalBiochemical Journal
Volume473
Issue number10
DOIs
Publication statusPublished - 11 May 2016

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Polyubiquitin
Ubiquitination
Ubiquitin
Substrates
Proteins
Recombinant Proteins
Topology
Research

Keywords

  • atypical
  • chemical biology
  • chemoenzymatic
  • isopeptide
  • ligation
  • post-translational modification
  • semisynthesis
  • ubiquitin
  • ubiquitination
  • ubiquitylation

Cite this

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title = "Chemical Ubiquitination for Decrypting a Cellular Code",
abstract = "The modification of proteins with ubiquitin (Ub) is an important regulator of eukaryotic biology and deleterious perturbation of this process is widely linked to the onset of various diseases. The regulatory capacity of the Ub signal is high and, in part, arises from the capability of Ub to be enzymatically polymerised to form polyubiquitin (polyUb) chains of 8 different linkage types. These distinct polyUb topologies can then be site-specifically conjugated to substrate proteins to elicit a number of cellular outcomes. Therefore, to further elucidate the biological significance of substrate ubiquitination, methodologies that allow the production of defined polyUb species and substrate proteins that are site-specifically modified with them are essential to progress our understanding. Many chemically inspired methods have recently emerged which fulfil many of the criteria necessary towards achieving deeper insight into Ub biology. With a view to providing immediate impact to traditional biology research labs, the aim of this review is to provide an overview of the techniques that are available for preparing Ub conjugates and polyUb chains with focus on approaches that use recombinant protein building blocks. These approaches either produce a native isopeptide, or analogue thereof, that can be hydrolyzable or non-hydrolyzable by deubiquitinases. The most significant biological insights that have already been garnered using such approaches will also be summarized.",
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Chemical Ubiquitination for Decrypting a Cellular Code. / Stanley, Mathew; Virdee, Satpal (Lead / Corresponding author).

In: Biochemical Journal, Vol. 473, No. 10, 11.05.2016, p. 1297-1314.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Chemical Ubiquitination for Decrypting a Cellular Code

AU - Stanley, Mathew

AU - Virdee, Satpal

N1 - This work was supported by the Scottish Funding Council and the Medical Research Council [grant number MC_UU_12016/8 (to S.V and M.S.)].

PY - 2016/5/11

Y1 - 2016/5/11

N2 - The modification of proteins with ubiquitin (Ub) is an important regulator of eukaryotic biology and deleterious perturbation of this process is widely linked to the onset of various diseases. The regulatory capacity of the Ub signal is high and, in part, arises from the capability of Ub to be enzymatically polymerised to form polyubiquitin (polyUb) chains of 8 different linkage types. These distinct polyUb topologies can then be site-specifically conjugated to substrate proteins to elicit a number of cellular outcomes. Therefore, to further elucidate the biological significance of substrate ubiquitination, methodologies that allow the production of defined polyUb species and substrate proteins that are site-specifically modified with them are essential to progress our understanding. Many chemically inspired methods have recently emerged which fulfil many of the criteria necessary towards achieving deeper insight into Ub biology. With a view to providing immediate impact to traditional biology research labs, the aim of this review is to provide an overview of the techniques that are available for preparing Ub conjugates and polyUb chains with focus on approaches that use recombinant protein building blocks. These approaches either produce a native isopeptide, or analogue thereof, that can be hydrolyzable or non-hydrolyzable by deubiquitinases. The most significant biological insights that have already been garnered using such approaches will also be summarized.

AB - The modification of proteins with ubiquitin (Ub) is an important regulator of eukaryotic biology and deleterious perturbation of this process is widely linked to the onset of various diseases. The regulatory capacity of the Ub signal is high and, in part, arises from the capability of Ub to be enzymatically polymerised to form polyubiquitin (polyUb) chains of 8 different linkage types. These distinct polyUb topologies can then be site-specifically conjugated to substrate proteins to elicit a number of cellular outcomes. Therefore, to further elucidate the biological significance of substrate ubiquitination, methodologies that allow the production of defined polyUb species and substrate proteins that are site-specifically modified with them are essential to progress our understanding. Many chemically inspired methods have recently emerged which fulfil many of the criteria necessary towards achieving deeper insight into Ub biology. With a view to providing immediate impact to traditional biology research labs, the aim of this review is to provide an overview of the techniques that are available for preparing Ub conjugates and polyUb chains with focus on approaches that use recombinant protein building blocks. These approaches either produce a native isopeptide, or analogue thereof, that can be hydrolyzable or non-hydrolyzable by deubiquitinases. The most significant biological insights that have already been garnered using such approaches will also be summarized.

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