Restoration of potent protein-tyrosine phosphatase activity into the membrane-distal domain of receptor protein-tyrosine phosphatase α

Arjan Buist, Yan Ling Zhang, Yen Fang Keng, Li Wu, Zhong-Yin Zhang, Jeroen Den Hertog

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Most transmembrane, receptor-like protein-tyrosine phosphatases (RPTPs) contain two cytoplasmic catalytic protein-tyrosine phosphatase (PTP) domains, of which the membrane-proximal domain, D1, contains the majority of the activity, while the membrane-distal domain, D2, exhibits little or no activity. We have investigated the structural basis for reduced activity in RPTP-D2s, using RPTPα as a model system. Sequence alignment of PTP domains indicated that two motifs, the KNRY motif and the WpD motif, are highly conserved in all PTP domains, but not in RPTP-D2s. In RPTPα-D2, the Tyr in the KNRY motif is substituted by Val (position 555) and the Asp in the WpD motif by Glu (position 690). Mutation of Va1555 and Glu690 had synergistic effects on RPTPα-D2 activity, in that the PTP activity of RPTPα-D2- V555Y/E690D was greatly enhanced to levels that were similar to or approaching those of RPTPα-D1. Therefore, Va1555 and Glu690 are responsible in large part for reduced RPTPα-D2 activity. In addition, we established that the increased PTP activity is due to restoration of effective transition-state stabilization in RPTPα-D2-V555Y/E690D. Since the KNRY motif and the WpD motif are mutated in all RPTP-D2s, it is highly unlikely, due to lack of transition-state stabilization, that the residual RPTP-D2 catalytic activity plays a role in the function of RPTPs.

Original languageEnglish (US)
Pages (from-to)914-922
Number of pages9
JournalBiochemistry
Volume38
Issue number3
DOIs
StatePublished - Jan 19 1999
Externally publishedYes

Fingerprint

Receptor-Like Protein Tyrosine Phosphatases
Protein Tyrosine Phosphatases
Restoration
Membranes
Stabilization
Sequence Alignment

ASJC Scopus subject areas

  • Biochemistry

Cite this

Restoration of potent protein-tyrosine phosphatase activity into the membrane-distal domain of receptor protein-tyrosine phosphatase α. / Buist, Arjan; Zhang, Yan Ling; Keng, Yen Fang; Wu, Li; Zhang, Zhong-Yin; Den Hertog, Jeroen.

In: Biochemistry, Vol. 38, No. 3, 19.01.1999, p. 914-922.

Research output: Contribution to journalArticle

Buist, Arjan ; Zhang, Yan Ling ; Keng, Yen Fang ; Wu, Li ; Zhang, Zhong-Yin ; Den Hertog, Jeroen. / Restoration of potent protein-tyrosine phosphatase activity into the membrane-distal domain of receptor protein-tyrosine phosphatase α. In: Biochemistry. 1999 ; Vol. 38, No. 3. pp. 914-922.
@article{39cd0794da58417ca76d607fb2ef8ccb,
title = "Restoration of potent protein-tyrosine phosphatase activity into the membrane-distal domain of receptor protein-tyrosine phosphatase α",
abstract = "Most transmembrane, receptor-like protein-tyrosine phosphatases (RPTPs) contain two cytoplasmic catalytic protein-tyrosine phosphatase (PTP) domains, of which the membrane-proximal domain, D1, contains the majority of the activity, while the membrane-distal domain, D2, exhibits little or no activity. We have investigated the structural basis for reduced activity in RPTP-D2s, using RPTPα as a model system. Sequence alignment of PTP domains indicated that two motifs, the KNRY motif and the WpD motif, are highly conserved in all PTP domains, but not in RPTP-D2s. In RPTPα-D2, the Tyr in the KNRY motif is substituted by Val (position 555) and the Asp in the WpD motif by Glu (position 690). Mutation of Va1555 and Glu690 had synergistic effects on RPTPα-D2 activity, in that the PTP activity of RPTPα-D2- V555Y/E690D was greatly enhanced to levels that were similar to or approaching those of RPTPα-D1. Therefore, Va1555 and Glu690 are responsible in large part for reduced RPTPα-D2 activity. In addition, we established that the increased PTP activity is due to restoration of effective transition-state stabilization in RPTPα-D2-V555Y/E690D. Since the KNRY motif and the WpD motif are mutated in all RPTP-D2s, it is highly unlikely, due to lack of transition-state stabilization, that the residual RPTP-D2 catalytic activity plays a role in the function of RPTPs.",
author = "Arjan Buist and Zhang, {Yan Ling} and Keng, {Yen Fang} and Li Wu and Zhong-Yin Zhang and {Den Hertog}, Jeroen",
year = "1999",
month = "1",
day = "19",
doi = "10.1021/bi981936b",
language = "English (US)",
volume = "38",
pages = "914--922",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

T1 - Restoration of potent protein-tyrosine phosphatase activity into the membrane-distal domain of receptor protein-tyrosine phosphatase α

AU - Buist, Arjan

AU - Zhang, Yan Ling

AU - Keng, Yen Fang

AU - Wu, Li

AU - Zhang, Zhong-Yin

AU - Den Hertog, Jeroen

PY - 1999/1/19

Y1 - 1999/1/19

N2 - Most transmembrane, receptor-like protein-tyrosine phosphatases (RPTPs) contain two cytoplasmic catalytic protein-tyrosine phosphatase (PTP) domains, of which the membrane-proximal domain, D1, contains the majority of the activity, while the membrane-distal domain, D2, exhibits little or no activity. We have investigated the structural basis for reduced activity in RPTP-D2s, using RPTPα as a model system. Sequence alignment of PTP domains indicated that two motifs, the KNRY motif and the WpD motif, are highly conserved in all PTP domains, but not in RPTP-D2s. In RPTPα-D2, the Tyr in the KNRY motif is substituted by Val (position 555) and the Asp in the WpD motif by Glu (position 690). Mutation of Va1555 and Glu690 had synergistic effects on RPTPα-D2 activity, in that the PTP activity of RPTPα-D2- V555Y/E690D was greatly enhanced to levels that were similar to or approaching those of RPTPα-D1. Therefore, Va1555 and Glu690 are responsible in large part for reduced RPTPα-D2 activity. In addition, we established that the increased PTP activity is due to restoration of effective transition-state stabilization in RPTPα-D2-V555Y/E690D. Since the KNRY motif and the WpD motif are mutated in all RPTP-D2s, it is highly unlikely, due to lack of transition-state stabilization, that the residual RPTP-D2 catalytic activity plays a role in the function of RPTPs.

AB - Most transmembrane, receptor-like protein-tyrosine phosphatases (RPTPs) contain two cytoplasmic catalytic protein-tyrosine phosphatase (PTP) domains, of which the membrane-proximal domain, D1, contains the majority of the activity, while the membrane-distal domain, D2, exhibits little or no activity. We have investigated the structural basis for reduced activity in RPTP-D2s, using RPTPα as a model system. Sequence alignment of PTP domains indicated that two motifs, the KNRY motif and the WpD motif, are highly conserved in all PTP domains, but not in RPTP-D2s. In RPTPα-D2, the Tyr in the KNRY motif is substituted by Val (position 555) and the Asp in the WpD motif by Glu (position 690). Mutation of Va1555 and Glu690 had synergistic effects on RPTPα-D2 activity, in that the PTP activity of RPTPα-D2- V555Y/E690D was greatly enhanced to levels that were similar to or approaching those of RPTPα-D1. Therefore, Va1555 and Glu690 are responsible in large part for reduced RPTPα-D2 activity. In addition, we established that the increased PTP activity is due to restoration of effective transition-state stabilization in RPTPα-D2-V555Y/E690D. Since the KNRY motif and the WpD motif are mutated in all RPTP-D2s, it is highly unlikely, due to lack of transition-state stabilization, that the residual RPTP-D2 catalytic activity plays a role in the function of RPTPs.

UR - http://www.scopus.com/inward/record.url?scp=0033579927&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033579927&partnerID=8YFLogxK

U2 - 10.1021/bi981936b

DO - 10.1021/bi981936b

M3 - Article

C2 - 9893986

AN - SCOPUS:0033579927

VL - 38

SP - 914

EP - 922

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 3

ER -