Structural basis for the specific interaction of lysine-containing proline-rich peptides with the N-terminal SH3 domain of c-Crk

Xiaodong Wu, Beatrice Knudsen, Stephan M. Feller, Jie Zheng, Andrej Sali, David Cowburn, Hidesaburo Hanafusa, John Kuriyan

Research output: Contribution to journalArticle

203 Citations (Scopus)

Abstract

Background: Proline-rich segments in the guanine nucleotide exchange factor C3G bind much more strongly to the N-terminal Src homology 3 domain (SH3-N) of the proto-oncogene product c-Crk than to other SH3 domains. The presence of a lysine instead of an arginine in the peptides derived from C3G appears to be crucial for this specificity towards c-Crk. Results In order to understand the chemical basis of this specificity we have determined the crystal structure of Crk SH3-N in complex with a high affinity peptide from C3G (PPPALPPKKR, Kd ∼2 μM) at 1.5 å resolution. The peptide adopts a polyproline type II helix that binds, as dictated by electrostatic complementarity, in reversed orientation relative to the orientation seen in the earliest structures of SH3-peptide complexes. A lysine in the C3G peptide is tightly coordinated by three acidic residues in the SH3 domain. In contrast, the co-crystal structure of c-Crk SH3-N and a peptide containing an arginine at the equivalent position (determined at 1.9 å resolution) reveals non-optimal geometry for the arginine and increased disorder. Conclusion The c-Crk SH3 domain engages in an unusual lysine-specific interaction that is rarely seen in protein structures, and which appears to be a key determinant of its unique ability to bind the C3G peptides with high affinity.

Original languageEnglish (US)
Pages (from-to)215-226
Number of pages12
JournalStructure
Volume3
Issue number2
DOIs
StatePublished - 1995
Externally publishedYes

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src Homology Domains
Proline
Lysine
Peptides
Arginine
Guanine Nucleotide-Releasing Factor 2
Proto-Oncogenes
Oncogene Proteins
Static Electricity

Keywords

  • c-Crk
  • peptide binding
  • polyproline helix
  • SH3 domain

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Structural basis for the specific interaction of lysine-containing proline-rich peptides with the N-terminal SH3 domain of c-Crk. / Wu, Xiaodong; Knudsen, Beatrice; Feller, Stephan M.; Zheng, Jie; Sali, Andrej; Cowburn, David; Hanafusa, Hidesaburo; Kuriyan, John.

In: Structure, Vol. 3, No. 2, 1995, p. 215-226.

Research output: Contribution to journalArticle

Wu, Xiaodong ; Knudsen, Beatrice ; Feller, Stephan M. ; Zheng, Jie ; Sali, Andrej ; Cowburn, David ; Hanafusa, Hidesaburo ; Kuriyan, John. / Structural basis for the specific interaction of lysine-containing proline-rich peptides with the N-terminal SH3 domain of c-Crk. In: Structure. 1995 ; Vol. 3, No. 2. pp. 215-226.
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abstract = "Background: Proline-rich segments in the guanine nucleotide exchange factor C3G bind much more strongly to the N-terminal Src homology 3 domain (SH3-N) of the proto-oncogene product c-Crk than to other SH3 domains. The presence of a lysine instead of an arginine in the peptides derived from C3G appears to be crucial for this specificity towards c-Crk. Results In order to understand the chemical basis of this specificity we have determined the crystal structure of Crk SH3-N in complex with a high affinity peptide from C3G (PPPALPPKKR, Kd ∼2 μM) at 1.5 {\aa} resolution. The peptide adopts a polyproline type II helix that binds, as dictated by electrostatic complementarity, in reversed orientation relative to the orientation seen in the earliest structures of SH3-peptide complexes. A lysine in the C3G peptide is tightly coordinated by three acidic residues in the SH3 domain. In contrast, the co-crystal structure of c-Crk SH3-N and a peptide containing an arginine at the equivalent position (determined at 1.9 {\aa} resolution) reveals non-optimal geometry for the arginine and increased disorder. Conclusion The c-Crk SH3 domain engages in an unusual lysine-specific interaction that is rarely seen in protein structures, and which appears to be a key determinant of its unique ability to bind the C3G peptides with high affinity.",
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AU - Zheng, Jie

AU - Sali, Andrej

AU - Cowburn, David

AU - Hanafusa, Hidesaburo

AU - Kuriyan, John

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N2 - Background: Proline-rich segments in the guanine nucleotide exchange factor C3G bind much more strongly to the N-terminal Src homology 3 domain (SH3-N) of the proto-oncogene product c-Crk than to other SH3 domains. The presence of a lysine instead of an arginine in the peptides derived from C3G appears to be crucial for this specificity towards c-Crk. Results In order to understand the chemical basis of this specificity we have determined the crystal structure of Crk SH3-N in complex with a high affinity peptide from C3G (PPPALPPKKR, Kd ∼2 μM) at 1.5 å resolution. The peptide adopts a polyproline type II helix that binds, as dictated by electrostatic complementarity, in reversed orientation relative to the orientation seen in the earliest structures of SH3-peptide complexes. A lysine in the C3G peptide is tightly coordinated by three acidic residues in the SH3 domain. In contrast, the co-crystal structure of c-Crk SH3-N and a peptide containing an arginine at the equivalent position (determined at 1.9 å resolution) reveals non-optimal geometry for the arginine and increased disorder. Conclusion The c-Crk SH3 domain engages in an unusual lysine-specific interaction that is rarely seen in protein structures, and which appears to be a key determinant of its unique ability to bind the C3G peptides with high affinity.

AB - Background: Proline-rich segments in the guanine nucleotide exchange factor C3G bind much more strongly to the N-terminal Src homology 3 domain (SH3-N) of the proto-oncogene product c-Crk than to other SH3 domains. The presence of a lysine instead of an arginine in the peptides derived from C3G appears to be crucial for this specificity towards c-Crk. Results In order to understand the chemical basis of this specificity we have determined the crystal structure of Crk SH3-N in complex with a high affinity peptide from C3G (PPPALPPKKR, Kd ∼2 μM) at 1.5 å resolution. The peptide adopts a polyproline type II helix that binds, as dictated by electrostatic complementarity, in reversed orientation relative to the orientation seen in the earliest structures of SH3-peptide complexes. A lysine in the C3G peptide is tightly coordinated by three acidic residues in the SH3 domain. In contrast, the co-crystal structure of c-Crk SH3-N and a peptide containing an arginine at the equivalent position (determined at 1.9 å resolution) reveals non-optimal geometry for the arginine and increased disorder. Conclusion The c-Crk SH3 domain engages in an unusual lysine-specific interaction that is rarely seen in protein structures, and which appears to be a key determinant of its unique ability to bind the C3G peptides with high affinity.

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