Structure-based thermodynamic analysis of caspases reveals key residues for dimerization and activity

Autoren

Stefano Piana
Marialore Sulpizi
Ursula Rothlisberger

DOI

10.1021/bi034032l

eISSN

1520-4995

ISSN

0006-2960

Ausgabe der Veröffentlichung

29

Zeitschrift

Biochemistry

Sprache

en

Online publication date

2003

Paginierung

8720 - 8728

Datum der Veröffentlichung

2003

Status

Published

Herausgeber

American Chemical Society (ACS)

Herausgeber URL

http://dx.doi.org/10.1021/bi034032l

Datum der Datenerfassung

2021

Titel

Structure-Based Thermodynamic Analysis of Caspases Reveals Key Residues for Dimerization and Activity

Ausgabe der Zeitschrift

42

Data source: Crossref

Abstract

Cysteine-dependent aspartic proteases (caspases) are a family of enzymes which play a crucial role in apoptosis. Caspases accumulate in eukaryotic cells in the form of low-activity proenzyme precursors. Proteolytic cleavage of specific sites triggers conformational changes that lead to full activation and thus to the initiation of the apoptotic cascade. Several experimental observations suggest that dimerization is crucial for activity and regulation, but the underlying molecular mechanisms have not yet been completely resolved. In this work, we have used a structure-based thermodynamic analysis method [Edgcomb, S. P., and Murphy, K. P. (2000) Curr. Opin. Biotechnol. 11, 62-66] to calculate the free energy of association and folding for all the caspases and procaspases whose structures are known at present. In all cases, analysis of the single-residue contributions to the dimerization energy shows that 30-50% of the dimer stability originates from the highly specific interaction of 12-14 residues located at the N- and C-termini of the large and small subunits, respectively. Moreover, our calculations indicate that these residues are also critical for stabilizing the conformation of the active site loops, which in turn is crucial for the binding of substrates and inhibitors. Thus, our results help to rationalize the relation between dimerization and activity in this important class of enzymes and can be used as a starting point for an active manipulation of the monomer-dimer equilibrium for preparatory and regulatory purposes.

Addresses

Institute of Molecular and Biological Chemistry, Federal Institute of Technology (EPFL), 1015 Lausanne, Switzerland.

Autoren

Stefano Piana
Marialore Sulpizi
Ursula Rothlisberger

DOI

10.1021/bi034032l

eISSN

1520-4995

Externe Identifier

PubMed Identifier: 12873132

Open access

false

ISSN

0006-2960

Ausgabe der Veröffentlichung

29

Zeitschrift

Biochemistry

Schlüsselwörter

Streptomyces
Cysteine
HIV Protease
Caspases
Histidine
Temperature
Apoptosis
Binding Sites
Enzyme Activation
Amino Acid Sequence
Protein Conformation
Protein Structure, Tertiary
Protein Binding
Protein Folding
Sequence Homology, Amino Acid
Dimerization
Kinetics
Hydrogen Bonding
Thermodynamics
Models, Biological
Models, Molecular
Molecular Sequence Data
Caspase 3
Caspase 7

Sprache

eng

Medium

Print

Paginierung

8720 - 8728

Datum der Veröffentlichung

2003

Status

Published

Datum der Datenerfassung

2003

Titel

Structure-based thermodynamic analysis of caspases reveals key residues for dimerization and activity.

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

42

Data source: Europe PubMed Central

Abstract

Cysteine-dependent aspartic proteases (caspases) are a family of enzymes which play a crucial role in apoptosis. Caspases accumulate in eukaryotic cells in the form of low-activity proenzyme precursors. Proteolytic cleavage of specific sites triggers conformational changes that lead to full activation and thus to the initiation of the apoptotic cascade. Several experimental observations suggest that dimerization is crucial for activity and regulation, but the underlying molecular mechanisms have not yet been completely resolved. In this work, we have used a structure-based thermodynamic analysis method [Edgcomb, S. P., and Murphy, K. P. (2000) Curr. Opin. Biotechnol. 11, 62-66] to calculate the free energy of association and folding for all the caspases and procaspases whose structures are known at present. In all cases, analysis of the single-residue contributions to the dimerization energy shows that 30-50% of the dimer stability originates from the highly specific interaction of 12-14 residues located at the N- and C-termini of the large and small subunits, respectively. Moreover, our calculations indicate that these residues are also critical for stabilizing the conformation of the active site loops, which in turn is crucial for the binding of substrates and inhibitors. Thus, our results help to rationalize the relation between dimerization and activity in this important class of enzymes and can be used as a starting point for an active manipulation of the monomer-dimer equilibrium for preparatory and regulatory purposes.

Autoren

Stefano Piana
Marialore Sulpizi
Ursula Rothlisberger

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/12873132

DOI

10.1021/bi034032l

ISSN

0006-2960

Ausgabe der Veröffentlichung

29

Zeitschrift

Biochemistry

Schlüsselwörter

Amino Acid Sequence
Apoptosis
Binding Sites
Caspase 3
Caspase 7
Caspases
Cysteine
Dimerization
Enzyme Activation
HIV Protease
Histidine
Hydrogen Bonding
Kinetics
Models, Biological
Models, Molecular
Molecular Sequence Data
Protein Binding
Protein Conformation
Protein Folding
Protein Structure, Tertiary
Sequence Homology, Amino Acid
Streptomyces
Temperature
Thermodynamics

Sprache

eng

Country

United States

Paginierung

8720 - 8728

Datum der Veröffentlichung

2003

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2003

Titel

Structure-based thermodynamic analysis of caspases reveals key residues for dimerization and activity.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

42

Data source: PubMed

Structure-based thermodynamic analysis of caspases reveals key residues for dimerization and activity

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