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The SH2 domains of inositol polyphosphate 5-phosphatases SHIP1 and SHIP2 have similar ligand specificity but different binding kinetics.

Abstract：

:SH2 domain-containing inositol 5-phosphatases 1 (SHIP1) and 2 (SHIP2) are structurally similar proteins that catalyze the degradation of lipid secondary messenger phosphatidylinositol 3,4,5-triphosphate to produce phosphatidylinositol 3,4-diphosphate. Despite their high sequence identity (51%), SHIP1 and SHIP2 share little overlap in their in vivo functions. In this work, the sequence specificity of the SHIP2 SH2 domain was systematically defined through the screening of a combinatorial pY peptide library. Comparison of its specificity profile with that of the SHIP1 SH2 domain showed that the two SH2 domains have similar specificities, both recognizing pY peptides of the consensus sequence pY[S/Y][L/Y/M][L/M/I/V], although there are also subtle differences such as the tolerance of an arginine at the pY + 1 position by the SHIP2 but not SHIP1 SH2 domain. Surface plasmon resonance analysis of their interaction with various pY peptides suggested that the two domains have similar binding affinities but dramatically different binding kinetics, with the SHIP1 SH2 domain having fast association and dissociation rates while the SHIP2 domain showing apparent slow-binding behavior. Site-directed mutagenesis and kinetic studies indicated that the SHIP2 SH2 domain exists as a mixture of two conformational isomers. The major, inactive isomer apparently contains two cis peptidyl-prolyl bonds at positions 88 and 105, whereas the minor, active isomer has both proline residues in their trans configuration. Cis-trans isomerization of the peptidyl-prolyl bonds may provide a potential mechanism for regulating the interaction between SHIP2 and pY proteins. These data suggest that a combination of tissue distribution, specificity, and kinetic differences is likely responsible for their in vivo functional differences.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Zhang Y,Wavreille AS,Kunys AR,Pei D

doi

10.1021/bi9012462

subject

Has Abstract

pub_date

2009-11-24 00:00:00

pages

11075-83

issue

eissn

0006-2960

issn

1520-4995

journal_volume

pub_type

杂志文章

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The SH2 domains of inositol polyphosphate 5-phosphatases SHIP1 and SHIP2 have similar ligand specificity but different binding kinetics.