Title:SHP Family Protein Tyrosine Phosphatases Adopt Canonical Active-Site Conformations in the Apo and Phosphate-Bound States
Volume: 20
Issue: 9
Author(s): Nilda L. Alicea-Velazquez and Titus J. Boggon
Affiliation:
Keywords:
Protein tyrosine phosphatase, WPD loop, conformational changes, cytokine signaling.
Abstract: Protein tyrosine phosphatase (PTP) catalytic domains undergo a series of conformational changes in order to
mediate dephosphorylation of their tyrosine phosphorylated substrates. An important conformational change occurs in the
Tryptophan-Proline-Aspartic acid (WPD) loop, which contains the conserved catalytic aspartate. Upon substrate binding,
the WPD loop transitions from the ‘open’ to the ‘closed’ state, thus allowing optimal positioning of the catalytic aspartate
for substrate dephosphorylation. The dynamics of WPD loop conformational changes have previously been studied for
PTP1B, HePTP, and the bacterial phosphatase YopH, but have not yet been comprehensively studied for the nonreceptor
tyrosine phosphatase SHP-1 (PTPN6). To structurally describe the changes in WPD loop conformation in SHP-1, we have
determined the 1.4 Å crystal structure of the catalytic domain of SHP-1 in the Apo state and the 1.8 Å crystal structure of
the SHP-1 catalytic domain in complex with a phosphate ion. We provide structural analysis for the WPD loop closed
state of SHP phosphatases and the conformational changes that occur upon WPD loop closure.
