Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome

Simone Martinelli, Aurelio P. Nardozza, Silvia Delle Vigne, Gilda Sabetta, Paola Torreri, Gianfranco Bocchinfuso, Elisabetta Flex, Serenella Venanzi, Antonio Palleschi, Bruce D. Gelb, Gianni Cesareni, Lorenzo Stella, Luisa Castagnoli, Marco Tartaglia

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Activating mutations in PTPN11 cause Noonan syndrome, the most common nonchromosomal disorder affecting development and growth. PTPN11 encodes SHP2, an Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase that positively modulates RAS function. Here, we characterized functionally all possible amino acid substitutions arising from single-base changes affecting codons 62 and 63 to explore the molecular mechanisms lying behind the largely invariant occurrence of the Y62D and Y63C substitutions recurring in Noonan syndrome. We provide structural and biochemical data indicating that the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase (PTP) domains is perturbed in both mutants as a result of an extensive structural rearrangement of the N-SH2 domain. Most mutations affecting Tyr 63exerted an unpredicted disrupting effect on the structure of the N-SH2 phosphopeptide-binding cleft mediating the interaction of SHP2 with signaling partners. Among all the amino acid changes affecting that codon, the disease-causing mutation was the only substitution that perturbed the stability of the inactive conformation of SHP2 without severely impairing proper phosphopeptide binding of N-SH2. On the other hand, the disruptive effect of the Y62D change on the autoinhibited conformation of the protein was balanced, in part, by less efficient binding properties of the mutant. Overall, our data demonstrate that the selection-by-function mechanism acting as driving force for PTPN11 mutations affecting codons 62 and 63 implies balancing of counteracting effects operating on the allosteric control of the function of SHP2.

Original languageEnglish
Pages (from-to)27066-27077
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number32
DOIs
Publication statusPublished - Aug 3 2012

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SH2 Domain-Containing Protein Tyrosine Phosphatases
Noonan Syndrome
Protein Phosphatase 2
Protein Tyrosine Phosphatases
Phosphopeptides
Substitution reactions
Codon
Mutation
Conformations
Amino Acids
Protein Conformation
src Homology Domains
Amino Acid Substitution
Growth and Development
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. / Martinelli, Simone; Nardozza, Aurelio P.; Vigne, Silvia Delle; Sabetta, Gilda; Torreri, Paola; Bocchinfuso, Gianfranco; Flex, Elisabetta; Venanzi, Serenella; Palleschi, Antonio; Gelb, Bruce D.; Cesareni, Gianni; Stella, Lorenzo; Castagnoli, Luisa; Tartaglia, Marco.

In: Journal of Biological Chemistry, Vol. 287, No. 32, 03.08.2012, p. 27066-27077.

Research output: Contribution to journalArticle

Martinelli, S, Nardozza, AP, Vigne, SD, Sabetta, G, Torreri, P, Bocchinfuso, G, Flex, E, Venanzi, S, Palleschi, A, Gelb, BD, Cesareni, G, Stella, L, Castagnoli, L & Tartaglia, M 2012, 'Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome', Journal of Biological Chemistry, vol. 287, no. 32, pp. 27066-27077. https://doi.org/10.1074/jbc.M112.350231
Martinelli, Simone ; Nardozza, Aurelio P. ; Vigne, Silvia Delle ; Sabetta, Gilda ; Torreri, Paola ; Bocchinfuso, Gianfranco ; Flex, Elisabetta ; Venanzi, Serenella ; Palleschi, Antonio ; Gelb, Bruce D. ; Cesareni, Gianni ; Stella, Lorenzo ; Castagnoli, Luisa ; Tartaglia, Marco. / Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 32. pp. 27066-27077.
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abstract = "Activating mutations in PTPN11 cause Noonan syndrome, the most common nonchromosomal disorder affecting development and growth. PTPN11 encodes SHP2, an Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase that positively modulates RAS function. Here, we characterized functionally all possible amino acid substitutions arising from single-base changes affecting codons 62 and 63 to explore the molecular mechanisms lying behind the largely invariant occurrence of the Y62D and Y63C substitutions recurring in Noonan syndrome. We provide structural and biochemical data indicating that the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase (PTP) domains is perturbed in both mutants as a result of an extensive structural rearrangement of the N-SH2 domain. Most mutations affecting Tyr 63exerted an unpredicted disrupting effect on the structure of the N-SH2 phosphopeptide-binding cleft mediating the interaction of SHP2 with signaling partners. Among all the amino acid changes affecting that codon, the disease-causing mutation was the only substitution that perturbed the stability of the inactive conformation of SHP2 without severely impairing proper phosphopeptide binding of N-SH2. On the other hand, the disruptive effect of the Y62D change on the autoinhibited conformation of the protein was balanced, in part, by less efficient binding properties of the mutant. Overall, our data demonstrate that the selection-by-function mechanism acting as driving force for PTPN11 mutations affecting codons 62 and 63 implies balancing of counteracting effects operating on the allosteric control of the function of SHP2.",
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T1 - Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome

AU - Martinelli, Simone

AU - Nardozza, Aurelio P.

AU - Vigne, Silvia Delle

AU - Sabetta, Gilda

AU - Torreri, Paola

AU - Bocchinfuso, Gianfranco

AU - Flex, Elisabetta

AU - Venanzi, Serenella

AU - Palleschi, Antonio

AU - Gelb, Bruce D.

AU - Cesareni, Gianni

AU - Stella, Lorenzo

AU - Castagnoli, Luisa

AU - Tartaglia, Marco

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N2 - Activating mutations in PTPN11 cause Noonan syndrome, the most common nonchromosomal disorder affecting development and growth. PTPN11 encodes SHP2, an Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase that positively modulates RAS function. Here, we characterized functionally all possible amino acid substitutions arising from single-base changes affecting codons 62 and 63 to explore the molecular mechanisms lying behind the largely invariant occurrence of the Y62D and Y63C substitutions recurring in Noonan syndrome. We provide structural and biochemical data indicating that the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase (PTP) domains is perturbed in both mutants as a result of an extensive structural rearrangement of the N-SH2 domain. Most mutations affecting Tyr 63exerted an unpredicted disrupting effect on the structure of the N-SH2 phosphopeptide-binding cleft mediating the interaction of SHP2 with signaling partners. Among all the amino acid changes affecting that codon, the disease-causing mutation was the only substitution that perturbed the stability of the inactive conformation of SHP2 without severely impairing proper phosphopeptide binding of N-SH2. On the other hand, the disruptive effect of the Y62D change on the autoinhibited conformation of the protein was balanced, in part, by less efficient binding properties of the mutant. Overall, our data demonstrate that the selection-by-function mechanism acting as driving force for PTPN11 mutations affecting codons 62 and 63 implies balancing of counteracting effects operating on the allosteric control of the function of SHP2.

AB - Activating mutations in PTPN11 cause Noonan syndrome, the most common nonchromosomal disorder affecting development and growth. PTPN11 encodes SHP2, an Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase that positively modulates RAS function. Here, we characterized functionally all possible amino acid substitutions arising from single-base changes affecting codons 62 and 63 to explore the molecular mechanisms lying behind the largely invariant occurrence of the Y62D and Y63C substitutions recurring in Noonan syndrome. We provide structural and biochemical data indicating that the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase (PTP) domains is perturbed in both mutants as a result of an extensive structural rearrangement of the N-SH2 domain. Most mutations affecting Tyr 63exerted an unpredicted disrupting effect on the structure of the N-SH2 phosphopeptide-binding cleft mediating the interaction of SHP2 with signaling partners. Among all the amino acid changes affecting that codon, the disease-causing mutation was the only substitution that perturbed the stability of the inactive conformation of SHP2 without severely impairing proper phosphopeptide binding of N-SH2. On the other hand, the disruptive effect of the Y62D change on the autoinhibited conformation of the protein was balanced, in part, by less efficient binding properties of the mutant. Overall, our data demonstrate that the selection-by-function mechanism acting as driving force for PTPN11 mutations affecting codons 62 and 63 implies balancing of counteracting effects operating on the allosteric control of the function of SHP2.

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