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New aspects of the phosphatase VHZ revealed by a high-resolution structure with vanadate and substrate screening

Vyacheslav I Kuznetsov1, Alvan C Hengge, Sean J Johnson

  • 1Department of Chemistry and Biochemistry, Utah State University, Logan, UT 84322-0300, USA.

Biochemistry
|November 14, 2012
PubMed

Insights

Human VHZ (VH1-related protein, Z member) is a small protein tyrosine phosphatase (PTP). Structural analysis reveals it acts as a tyrosine-specific PTP, distinct from dual-specificity phosphatases.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Enzymology

Background:

  • Human VHZ is a recently discovered, small protein tyrosine phosphatase (PTP).
  • It possesses minimal structural elements common to all PTPs.
  • Previous classifications suggested VHZ might be an atypical dual-specificity phosphatase (DSP).

Purpose of the Study:

  • To investigate the substrate specificity and structural characteristics of human VHZ.
  • To compare VHZ structure with other PTP family members.
  • To clarify the classification of VHZ within the PTP superfamily.

Main Methods:

  • Substrate screening analysis using 360 phosphorylated peptides.
  • X-ray crystallography to determine the VHZ-vanadate complex structure at 1.1 Å resolution.
  • Detailed structural comparison with classical tyrosine-specific PTPs and DSPs.

Main Results:

  • VHZ efficiently hydrolyzes phosphotyrosine (pY)-containing peptides.
  • VHZ shows no activity against phosphoserine (pS) or phosphothreonine (pT) peptides.
  • The crystal structure reveals a deep, narrow active site characteristic of tyrosine-specific PTPs, with a conformationally rigid IPD-loop and lacking substrate recognition domains.

Conclusions:

  • VHZ functions as a tyrosine-specific PTP.
  • Its unique structural features, including the rigid IPD-loop and absence of specific domains, differentiate it from classical PTPs.
  • VHZ should be classified as an atypical PTP, not an atypical DSP.

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