Reexamination of the recognition preference of the specificity pocket of the Abl SH3 domain

Fanny Santamaria, Zhibin Wu, Cyril Boulègue, G. Pál, Wuyuan Lu

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Src homology-3 (SH3) domains mediate important protein-protein interactions in a variety of normal and pathological cellular processes, thus providing an attractive target for the selective interference of SH3-dependent signaling events that govern these processes. Most SH3 domains recognize proline-rich peptides with low affinity and poor selectivity, and the goal to design potent and specific ligands for various SH3 domains remains elusive. Better understanding of the molecular basis for SH3 domain recognition is needed in order to design such ligands with potency and specificity. In this report, we seek to define a clear recognition preference of the specificity pocket of the Abl SH3 domain using targeted synthetic peptide libraries. High-resolution affinity panning coupled with mass spectrometric readout allows for quick identification of Trp as the preferred fourth residue in the decapeptide ligand APTWSPPPPP, which binds to Abl SH3 four times stronger than does the decapeptide containing Tyr or Phe in the fourth position. This finding is in contrast to several reports that Tyr is the only residue selected from phage displayed peptide libraries that interacts with the specificity pocket of Abl SH3. This simple, unbiased approach can fine-tune the affinity and selectivity of both natural and unnatural SH3 ligands whose consensus binding sequence has been pre-defined by combinatorial library methods.

Original languageEnglish
Pages (from-to)131-138
Number of pages8
JournalJournal of Molecular Recognition
Volume16
Issue number3
DOIs
Publication statusPublished - May 2003

Fingerprint

src Homology Domains
Ligands
Peptides
Peptide Library
Proteins
Bacteriophages
Proline
Consensus Sequence
Pathologic Processes

Keywords

  • Chemical protein synthesis
  • Peptide library
  • Protein-peptide recognition
  • SH3 domain
  • Solid phase peptide synthesis
  • Specificity

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Computer Vision and Pattern Recognition
  • Immunology
  • Molecular Biology

Cite this

Reexamination of the recognition preference of the specificity pocket of the Abl SH3 domain. / Santamaria, Fanny; Wu, Zhibin; Boulègue, Cyril; Pál, G.; Lu, Wuyuan.

In: Journal of Molecular Recognition, Vol. 16, No. 3, 05.2003, p. 131-138.

Research output: Contribution to journalArticle

Santamaria, Fanny ; Wu, Zhibin ; Boulègue, Cyril ; Pál, G. ; Lu, Wuyuan. / Reexamination of the recognition preference of the specificity pocket of the Abl SH3 domain. In: Journal of Molecular Recognition. 2003 ; Vol. 16, No. 3. pp. 131-138.
@article{0959b90c93b04d4a8ffe25e4429533e1,
title = "Reexamination of the recognition preference of the specificity pocket of the Abl SH3 domain",
abstract = "Src homology-3 (SH3) domains mediate important protein-protein interactions in a variety of normal and pathological cellular processes, thus providing an attractive target for the selective interference of SH3-dependent signaling events that govern these processes. Most SH3 domains recognize proline-rich peptides with low affinity and poor selectivity, and the goal to design potent and specific ligands for various SH3 domains remains elusive. Better understanding of the molecular basis for SH3 domain recognition is needed in order to design such ligands with potency and specificity. In this report, we seek to define a clear recognition preference of the specificity pocket of the Abl SH3 domain using targeted synthetic peptide libraries. High-resolution affinity panning coupled with mass spectrometric readout allows for quick identification of Trp as the preferred fourth residue in the decapeptide ligand APTWSPPPPP, which binds to Abl SH3 four times stronger than does the decapeptide containing Tyr or Phe in the fourth position. This finding is in contrast to several reports that Tyr is the only residue selected from phage displayed peptide libraries that interacts with the specificity pocket of Abl SH3. This simple, unbiased approach can fine-tune the affinity and selectivity of both natural and unnatural SH3 ligands whose consensus binding sequence has been pre-defined by combinatorial library methods.",
keywords = "Chemical protein synthesis, Peptide library, Protein-peptide recognition, SH3 domain, Solid phase peptide synthesis, Specificity",
author = "Fanny Santamaria and Zhibin Wu and Cyril Boul{\`e}gue and G. P{\'a}l and Wuyuan Lu",
year = "2003",
month = "5",
doi = "10.1002/jmr.620",
language = "English",
volume = "16",
pages = "131--138",
journal = "Journal of Molecular Recognition",
issn = "0952-3499",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - Reexamination of the recognition preference of the specificity pocket of the Abl SH3 domain

AU - Santamaria, Fanny

AU - Wu, Zhibin

AU - Boulègue, Cyril

AU - Pál, G.

AU - Lu, Wuyuan

PY - 2003/5

Y1 - 2003/5

N2 - Src homology-3 (SH3) domains mediate important protein-protein interactions in a variety of normal and pathological cellular processes, thus providing an attractive target for the selective interference of SH3-dependent signaling events that govern these processes. Most SH3 domains recognize proline-rich peptides with low affinity and poor selectivity, and the goal to design potent and specific ligands for various SH3 domains remains elusive. Better understanding of the molecular basis for SH3 domain recognition is needed in order to design such ligands with potency and specificity. In this report, we seek to define a clear recognition preference of the specificity pocket of the Abl SH3 domain using targeted synthetic peptide libraries. High-resolution affinity panning coupled with mass spectrometric readout allows for quick identification of Trp as the preferred fourth residue in the decapeptide ligand APTWSPPPPP, which binds to Abl SH3 four times stronger than does the decapeptide containing Tyr or Phe in the fourth position. This finding is in contrast to several reports that Tyr is the only residue selected from phage displayed peptide libraries that interacts with the specificity pocket of Abl SH3. This simple, unbiased approach can fine-tune the affinity and selectivity of both natural and unnatural SH3 ligands whose consensus binding sequence has been pre-defined by combinatorial library methods.

AB - Src homology-3 (SH3) domains mediate important protein-protein interactions in a variety of normal and pathological cellular processes, thus providing an attractive target for the selective interference of SH3-dependent signaling events that govern these processes. Most SH3 domains recognize proline-rich peptides with low affinity and poor selectivity, and the goal to design potent and specific ligands for various SH3 domains remains elusive. Better understanding of the molecular basis for SH3 domain recognition is needed in order to design such ligands with potency and specificity. In this report, we seek to define a clear recognition preference of the specificity pocket of the Abl SH3 domain using targeted synthetic peptide libraries. High-resolution affinity panning coupled with mass spectrometric readout allows for quick identification of Trp as the preferred fourth residue in the decapeptide ligand APTWSPPPPP, which binds to Abl SH3 four times stronger than does the decapeptide containing Tyr or Phe in the fourth position. This finding is in contrast to several reports that Tyr is the only residue selected from phage displayed peptide libraries that interacts with the specificity pocket of Abl SH3. This simple, unbiased approach can fine-tune the affinity and selectivity of both natural and unnatural SH3 ligands whose consensus binding sequence has been pre-defined by combinatorial library methods.

KW - Chemical protein synthesis

KW - Peptide library

KW - Protein-peptide recognition

KW - SH3 domain

KW - Solid phase peptide synthesis

KW - Specificity

UR - http://www.scopus.com/inward/record.url?scp=0038350592&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038350592&partnerID=8YFLogxK

U2 - 10.1002/jmr.620

DO - 10.1002/jmr.620

M3 - Article

C2 - 12833568

AN - SCOPUS:0038350592

VL - 16

SP - 131

EP - 138

JO - Journal of Molecular Recognition

JF - Journal of Molecular Recognition

SN - 0952-3499

IS - 3

ER -