Structure and mechanism of the phosphotyrosyl phosphatase activator

被引：43

作者：

Chao, Yang ^{[1
]}

Xing, Yongna ^{[1
]}

Chen, Yu ^{[1
]}

Xu, Yanhui ^{[1
]}

Lin, Zheng ^{[1
]}

Li, Zhu ^{[1
]}

Jeffrey, Philip D. ^{[1
]}

Stock, Jeffry B. ^{[1
]}

Shi, Yigong ^{[1
]}

机构：

[1] Princeton Univ, Dept Mol Biol, Lewis Thomas Lab, Princeton, NJ 08544 USA

来源：

MOLECULAR CELL | 2006年 / 23卷 / 04期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1016/j.molcel.2006.07.027

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Phosphotyrosyl phosphatase activator (PTPA), also known as PP2A phosphatase activator, is a conserved protein from yeast to human. Here we report the 1.9 angstrom crystal structure of human PTPA, which reveals a previously unreported fold consisting of three subdomains: core, lid, and linker. Structural analysis uncovers a highly conserved surface patch, which borders the three subdomains, and an associated deep pocket located between the core and the linker subdomains. The conserved surface patch and the deep pocket are responsible for binding to PP2A and ATP, respectively. PTPA and PP2A A-C dimer together constitute a composite ATPase. PTPA binding to PP2A results in a dramatic alteration of substrate specificity, with enhanced phosphotyrosine phosphatase activity and decreased phosphoserine phosphatase activity. This function of PTPA strictly depends on the composite ATPase activity. These observations reveal significant insights into the function and mechanism of PTPA and have important ramifications for understanding PP2A function.

引用

页码：535 / 546

页数：12

共 35 条

[1] A comparative study of the phosphotyrosyl phosphatase specificity of protein phosphatase type 2A and phosphotyrosyl phosphatase type 1B using phosphopeptides and the phosphoproteins p50/HS1, c-Fgr and Lyn [J].

Agostinis, P ;

DonellaDeana, A ;

VanHoof, C ;

Cesaro, L ;

Brunati, AM ;

Ruzzene, M ;

Merlevede, W ;

Pinna, LA ;

Goris, J .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 1996, 236 (02) :548-557

[2] Protein tyrosine phosphatases in the human genome [J].

Alonso, A ;

Sasin, J ;

Bottini, N ;

Friedberg, I ;

Osterman, A ;

Godzik, A ;

Hunter, T ;

Dixon, J ;

Mustelin, T .

CELL, 2004, 117 (06) :699-711

[3] HUMAN-LIVER PHOSPHATASE 2A - CDNA AND AMINO-ACID SEQUENCE OF 2 CATALYTIC SUBUNIT ISOTYPES [J].

ARINO, J ;

CHEE, WW ;

BRAUTIGAN, DL ;

MILLER, TB ;

JOHNSON, GL .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (12) :4252-4256

[4] INHIBITORY EFFECT OF A MARINE-SPONGE TOXIN, OKADAIC ACID, ON PROTEIN PHOSPHATASES - SPECIFICITY AND KINETICS [J].

BIALOJAN, C ;

TAKAI, A .

BIOCHEMICAL JOURNAL, 1988, 256 (01) :283-290

[5]

Brunger AT, 1998, ACTA CRYSTALLOGR D, V54, P905, DOI 10.1107/s0907444998003254

[6] ISOLATION AND CHARACTERIZATION OF A TYROSYL PHOSPHATASE ACTIVATOR FROM RABBIT SKELETAL-MUSCLE AND XENOPUS-LAEVIS OOCYTES [J].

CAYLA, X ;

GORIS, J ;

HERMANN, J ;

HENDRIX, P ;

OZON, R ;

MERLEVEDE, W .

BIOCHEMISTRY, 1990, 29 (03) :658-667

[7]

CAYLA X, 1994, J BIOL CHEM, V269, P15668

[8] PROTEIN SERINE THREONINE PHOSPHATASES - AN EXPANDING FAMILY [J].

COHEN, PTW ;

BREWIS, ND ;

HUGHES, V ;

MANN, DJ .

FEBS LETTERS, 1990, 268 (02) :355-359

[9] CRYSTAL-STRUCTURE OF THE CATALYTIC SUBUNIT OF HUMAN PROTEIN PHOSPHATASE-1 AND ITS COMPLEX WITH TUNGSTATE [J].

EGLOFF, MP ;

COHEN, PTW ;

REINEMER, P ;

BARFORD, D .

JOURNAL OF MOLECULAR BIOLOGY, 1995, 254 (05) :942-959

[10] A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo [J].

Fellner, T ;

Lackner, DH ;

Hombauer, H ;

Piribauer, P ;

Mudrak, I ;

Zaragoza, K ;

Juno, C ;

Ogris, E .

GENES & DEVELOPMENT, 2003, 17 (17) :2138-2150

← 1 2 3 4 →