Crystal structure of the BARD1 ankyrin repeat domain and its functional consequences

被引：32

作者：

Fox, David, III ^{[1
]}

Le Trong, Isolde ^{[2
,3
]}

Rajagopal, Ponni ^{[1
]}

Brzovic, Peter S. ^{[1
]}

Stenkamp, Ronald E. ^{[1
,2
,3
]}

Klevit, Rachel E. ^{[1
]}

机构：

[1] Univ Washington, Dept Biochem, Seattle, WA 98195 USA

[2] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA

[3] Univ Washington, Biomol Struct Ctr, Seattle, WA 98195 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2008年 / 283卷 / 30期

关键词：

D O I：

10.1074/jbc.M802333200

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：

BARD1 is the constitutive nuclear partner to the breast and ovarian cancer-specific tumor suppressor BRCA1. Together, they form a heterodimeric complex responsible for maintaining genomic stability through nuclear functions involving DNA damage signaling and repair, transcriptional regulation, and cell cycle control. We report the 2.0 angstrom structure of the BARD1 ankyrin repeat domain. The structure includes four ankyrin repeats with a non-canonical C-terminal capping ankyrin repeat and a well ordered extended loop preceding the first repeat. Conserved surface features show an acidic patch and an acidic pocket along the surface typically used by ankyrin repeat domains for binding cognate proteins. We also demonstrate that two reported mutations, N470S and V507M, in the ankyrin repeat domain do not result in observable structural defects. These results provide a structural basis for exploring the biological function of the ankyrin repeat domain and for modeling BARD1 isoforms.

引用

页码：21179 / 21186

页数：8

共 34 条

[21] The ankyrin repeat as molecular architecture for protein recognition [J].

Mosavi, LK ;

Cammett, TJ ;

Desrosiers, DC ;

Peng, ZY .

PROTEIN SCIENCE, 2004, 13 (06) :1435-1448

[22] Structure of the oncoprotein gankyrin in complex with S6 ATPase of the 26S proteasome [J].

Nakamura, Yoshihiro ;

Nakano, Kazumi ;

Umehara, Takashi ;

Kimura, Mayumi ;

Hayashizaki, Yoshihide ;

Tanaka, Akiko ;

Horikoshi, Masami ;

Padmanabhan, Balasundaram ;

Yokoyama, Shigeyuki .

STRUCTURE, 2007, 15 (02) :179-189

[23] Processing of X-ray diffraction data collected in oscillation mode [J].

Otwinowski, Z ;

Minor, W .

MACROMOLECULAR CRYSTALLOGRAPHY, PT A, 1997, 276 :307-326

[24] Optimal description of a protein structure in terms of multiple groups undergoing TLS motion [J].

Painter, J ;

Merritt, EA .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2006, 62 :439-450

[25] TLSMD web server for the generation of multi-group TLS models [J].

Painter, J ;

Merritt, EA .

JOURNAL OF APPLIED CRYSTALLOGRAPHY, 2006, 39 :109-111

[26] ARP/wARP and molecular replacement [J].

Perrakis, A ;

Harkiolaki, M ;

Wilson, KS ;

Lamzin, VS .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 2001, 57 :1445-1450

[27] The BARD1 Cys557Ser variant and breast cancer risk in Iceland [J].

Stacey, Simon N. ;

Sulem, Patrick ;

Johannsson, Oskar T. ;

Helgason, Agnar ;

Gudmundsson, Julius ;

Kostic, Jelena P. ;

Kristjansson, Kristleifur ;

Jonsdottir, Thora ;

Sigurdsson, Helgi ;

Hrafnkelsson, Jon ;

Johannsson, Jakob ;

Sveinsson, Thorarinn ;

Myrdal, Gardar ;

Grimsson, Hlynur Niels ;

Bergthorsson, Jon T. ;

Amundadottir, Laufey T. ;

Gulcher, Jeffrey R. ;

Thorsteinsdottir, Unnur ;

Kong, Augustine ;

Stefansson, Kari .

PLOS MEDICINE, 2006, 3 (07) :1103-1113

[28] Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers [J].

Thai, TH ;

Du, FH ;

Tsan, JT ;

Jin, Y ;

Phung, A ;

Spillman, MA ;

Massa, HF ;

Muller, CY ;

Ashfaq, R ;

Mathis, JM ;

Miller, DS ;

Trask, BJ ;

Baer, R ;

Bowcock, AM .

HUMAN MOLECULAR GENETICS, 1998, 7 (02) :195-202

[29] A truncated splice variant of human BARD1 that lacks the RING finger and ankyrin repeats [J].

Tsuzuki, M ;

Wu, WW ;

Nishikawa, H ;

Hayami, R ;

Oyake, D ;

Yabuki, Y ;

Fukuda, M ;

Ohta, T .

CANCER LETTERS, 2006, 233 (01) :108-116

[30]

US Cancer Statistics Working Group, 2007, US CANC STAT 2004 IN

← 1 2 3 4 →