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Noonan syndrome type I with PTPN11 3 bp deletion: Structure–function implications
Author(s) -
Lee Wen Hwa,
RaasRotschild Annick,
Miteva Maria A.,
Bolasco Giulia,
Rein Azaria,
Gillis David,
Vidaud Dominique,
Vidaud Michel,
Villoutreix Bruno O.,
Parfait Beatrice
Publication year - 2004
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20296
Subject(s) - ptpn11 , protein tyrosine phosphatase , phosphatase , mutant , noonan syndrome , gene , wild type , active site , mutation , biology , tyrosine , chemistry , genetics , enzyme , biochemistry , kras
Noonan syndrome was recently reported to be caused by mutations in the PTPN11 gene in 40% of the cases. This gene encodes the nonreceptor‐type protein tyrosine phosphatase SHP‐2 and has been shown to be self down‐regulated with the concurrency of two SH2 domains. Insertion of a specific loop (D′EF) from N‐terminal SH2 domain into the SHP‐2 active‐site is responsible for the reversible inhibition of the phosphatase activity. Here we report the first in frame trinucleotide deletion resulting in the removal of Aspartate 61 (D61del), a key residue of the N‐terminal SH2 D′EF loop. Energetic‐based structural analysis and electrostatic calculations carried out on the wild‐type and mutant proteins predict lower stability of the D′EF loop for the D61del variant as compared to the wild type indicating better access to the active site and most likely an enzyme activated for longer extent. Similar computations were performed on the previously functionally characterized gain‐of‐function D61Y mutant and similar behaviors were observed. The simulation data for the D61del and D61Y mutants suggest that both variants could yield more catalytic cycles than the wild‐type molecule in the same timespan because of the opening of the active site. It also supports the notion that D61 plays a major role for proper down‐regulation of the protein tyrosine phosphatase activity of SHP‐2. Proteins 2005. © 2004 Wiley‐Liss, Inc.