Tolerance of protein folding to a circular permutation in a PDZ domain

Greta Hultqvist, Avinash S. Punekar, Angela Morrone, Celestine N. Chi, Ake Engström, Maria Selmer (Lead / Corresponding author), Stefano Gianni (Lead / Corresponding author), Per Jemth (Lead / Corresponding author)

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Circular permutation is a common molecular mechanism for evolution of proteins. However, such re-arrangement of secondary structure connectivity may interfere with the folding mechanism causing accumulation of folding intermediates, which in turn can lead to misfolding. We solved the crystal structure and investigated the folding pathway of a circularly permuted variant of a PDZ domain, SAP97 PDZ2. Our data illustrate how well circular permutation may work as a mechanism for molecular evolution. The circular permutant retains the overall structure and function of the native protein domain. Further, unlike most examples in the literature, this circular permutant displays a folding mechanism that is virtually identical to that of the wild type. This observation contrasts with previous data on the circularly permuted PDZ2 domain from PTP-BL, for which the folding pathway was remarkably affected by the same mutation in sequence connectivity. The different effects of this circular permutation in two homologous proteins show the strong influence of sequence as compared to topology. Circular permutation, when peripheral to the major folding nucleus, may have little effect on folding pathways and could explain why, despite the dramatic change in primary structure, it is frequently tolerated by different protein folds.

Original languageEnglish
Pages (from-to)e50055
Number of pages11
JournalPLoS ONE
Volume7
Issue number11
DOIs
Publication statusPublished - 2012

Fingerprint

PDZ Domains
Protein folding
protein folding
Protein Folding
Molecular Evolution
Proteins
proteins
crystal structure
topology
Mutation
Crystal structure
Topology
mutation

Keywords

  • Adaptor Proteins, Signal Transducing/chemistry
  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Escherichia coli/genetics
  • Humans
  • Kinetics
  • Membrane Proteins/chemistry
  • Models, Molecular
  • Molecular Sequence Data
  • PDZ Domains
  • Peptides/chemistry
  • Protein Engineering
  • Protein Folding
  • Protein Stability
  • Protein Structure, Secondary
  • Protein Unfolding
  • Recombinant Proteins/chemistry
  • Structural Homology, Protein
  • Thermodynamics

Cite this

Hultqvist, G., Punekar, A. S., Morrone, A., Chi, C. N., Engström, A., Selmer, M., ... Jemth, P. (2012). Tolerance of protein folding to a circular permutation in a PDZ domain. PLoS ONE, 7(11), e50055. https://doi.org/10.1371/journal.pone.0050055
Hultqvist, Greta ; Punekar, Avinash S. ; Morrone, Angela ; Chi, Celestine N. ; Engström, Ake ; Selmer, Maria ; Gianni, Stefano ; Jemth, Per. / Tolerance of protein folding to a circular permutation in a PDZ domain. In: PLoS ONE. 2012 ; Vol. 7, No. 11. pp. e50055.
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Hultqvist, G, Punekar, AS, Morrone, A, Chi, CN, Engström, A, Selmer, M, Gianni, S & Jemth, P 2012, 'Tolerance of protein folding to a circular permutation in a PDZ domain', PLoS ONE, vol. 7, no. 11, pp. e50055. https://doi.org/10.1371/journal.pone.0050055

Tolerance of protein folding to a circular permutation in a PDZ domain. / Hultqvist, Greta; Punekar, Avinash S.; Morrone, Angela; Chi, Celestine N.; Engström, Ake; Selmer, Maria (Lead / Corresponding author); Gianni, Stefano (Lead / Corresponding author); Jemth, Per (Lead / Corresponding author).

In: PLoS ONE, Vol. 7, No. 11, 2012, p. e50055.

Research output: Contribution to journalArticle

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T1 - Tolerance of protein folding to a circular permutation in a PDZ domain

AU - Hultqvist, Greta

AU - Punekar, Avinash S.

AU - Morrone, Angela

AU - Chi, Celestine N.

AU - Engström, Ake

AU - Selmer, Maria

AU - Gianni, Stefano

AU - Jemth, Per

PY - 2012

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AB - Circular permutation is a common molecular mechanism for evolution of proteins. However, such re-arrangement of secondary structure connectivity may interfere with the folding mechanism causing accumulation of folding intermediates, which in turn can lead to misfolding. We solved the crystal structure and investigated the folding pathway of a circularly permuted variant of a PDZ domain, SAP97 PDZ2. Our data illustrate how well circular permutation may work as a mechanism for molecular evolution. The circular permutant retains the overall structure and function of the native protein domain. Further, unlike most examples in the literature, this circular permutant displays a folding mechanism that is virtually identical to that of the wild type. This observation contrasts with previous data on the circularly permuted PDZ2 domain from PTP-BL, for which the folding pathway was remarkably affected by the same mutation in sequence connectivity. The different effects of this circular permutation in two homologous proteins show the strong influence of sequence as compared to topology. Circular permutation, when peripheral to the major folding nucleus, may have little effect on folding pathways and could explain why, despite the dramatic change in primary structure, it is frequently tolerated by different protein folds.

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KW - Amino Acid Sequence

KW - Crystallography, X-Ray

KW - Escherichia coli/genetics

KW - Humans

KW - Kinetics

KW - Membrane Proteins/chemistry

KW - Models, Molecular

KW - Molecular Sequence Data

KW - PDZ Domains

KW - Peptides/chemistry

KW - Protein Engineering

KW - Protein Folding

KW - Protein Stability

KW - Protein Structure, Secondary

KW - Protein Unfolding

KW - Recombinant Proteins/chemistry

KW - Structural Homology, Protein

KW - Thermodynamics

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DO - 10.1371/journal.pone.0050055

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SP - e50055

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

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ER -