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PDBsum entry 4dgx
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References listed in PDB file
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Key reference
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Title
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Structural and mechanistic insights into leopard syndrome-Associated shp2 mutations.
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Authors
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Z.H.Yu,
J.Xu,
C.D.Walls,
L.Chen,
S.Zhang,
R.Zhang,
L.Wu,
L.Wang,
S.Liu,
Z.Y.Zhang.
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Ref.
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J Biol Chem, 2013,
288,
10472-10482.
[DOI no: ]
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PubMed id
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Abstract
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SHP2 is an allosteric phosphatase essential for growth factor-mediated Ras
activation. Germ-line mutations in SHP2 cause clinically similar LEOPARD and
Noonan syndromes, two of several autosomal-dominant conditions characterized by
gain-of-function mutations in the Ras pathway. Interestingly, Noonan syndrome
SHP2 mutants are constitutively active, whereas LEOPARD syndrome SHP2 mutants
exhibit reduced phosphatase activity. How do catalytically impaired LEOPARD
syndrome mutants engender gain-of-function phenotypes? Our study reveals that
LEOPARD syndrome mutations weaken the intramolecular interaction between the
N-SH2 and phosphatase domains, leading to a change in SHP2 molecular switching
mechanism. Consequently, LEOPARD syndrome SHP2 mutants bind upstream activators
preferentially and are hypersensitive to growth factor stimulation. They also
stay longer with scaffolding adapters, thus prolonging substrate turnover, which
compensates for the reduced phosphatase activity. The study provides a solid
framework for understanding how individual SHP2 mutations cause diseases.
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