Structural insights into the DNA-binding mechanism of BCL11A: The role of ZnF6

被引：1

作者：

Viennet, Thibault ^{[1
,2
,8
,9
]}

Yin, Maolu ^{[3
,4
,5
]}

Jayaraj, Abhilash ^{[1
,2
]}

Kim, Woojin ^{[3
]}

Sun, Zhen-Yu J. ^{[1
]}

Fujiwara, Yuko ^{[3
]}

Zhang, Kevin ^{[3
]}

Seruggia, Davide ^{[3
,6
,7
]}

Seo, Hyuk-Soo ^{[1
,2
]}

Dhe-Paganon, Sirano ^{[1
,2
]}

Orkin, Stuart H. ^{[3
,4
,5
]}

Arthanari, Haribabu ^{[1
,2
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[2] Harvard Med Sch, Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[3] Harvard Med Sch, Dana Farber Boston Childrens Canc & Blood Disorder, Boston, MA 02115 USA

[4] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

[5] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria

[6] St Anna Childrens Canc Res Inst CCRI, Vienna, Austria

[7] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria

[8] Aarhus Univ, Dept Chem, Aarhus, Denmark

[9] Aarhus Univ, iNANO, Aarhus, Denmark

来源：

STRUCTURE | 2024年 / 32卷 / 12期

基金：

美国国家卫生研究院;

关键词：

ZINC-FINGER PROTEIN; MOLECULAR-DYNAMICS SIMULATIONS; GREEK HEREDITARY PERSISTENCE; SICKLE-CELL-DISEASE; GAMMA-GLOBIN GENE; FETAL-HEMOGLOBIN; CRYSTAL-STRUCTURE; SIDE-CHAIN; RECOGNITION; DOMAINS;

D O I：

10.1016/j.str.2024.09.022

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：

The transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: a2g2) to adult hemoglobin (HbA: a2b2) during development. BCL11A binds at a cognate recognition site (TGACCA) in the g-globin gene promoter and represses its expression. DNA-binding is mediated by a triple zinc finger domain, designated ZnF456. Here, we report comprehensive investigation of ZnF456, leveraging X-ray crystallography and NMR to determine the structures in both the presence and absence of DNA. We delve into the dynamics and mode of interaction with DNA. Moreover, we discovered that the last zinc finger of BCL11A (ZnF6) plays a different role compared to ZnF4 and 5, providing a positive entropic contribution to DNA binding and g-globin gene repression. Comprehending the DNA binding mechanism of BCL11A opens avenues for the strategic, structure-based design of novel therapeutics targeting sickle cell disease and b-thalassemia.

引用

页码：2276 / 2286.e4

页数：16

共 71 条

[1] PHENIX: a comprehensive Python']Python-based system for macromolecular structure solution
Adams, Paul D.
Afonine, Pavel V.
Bunkoczi, Gabor
Chen, Vincent B.
Davis, Ian W.
Echols, Nathaniel
Headd, Jeffrey J.
Hung, Li-Wei
Kapral, Gary J.
Grosse-Kunstleve, Ralf W.
McCoy, Airlie J.
Moriarty, Nigel W.
Oeffner, Robert
Read, Randy J.
Richardson, David C.
Richardson, Jane S.
Terwilliger, Thomas C.
Zwart, Peter H.
[J]. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2010, 66 : 213 - 221
[2] When basic science reaches into rational therapeutic design: from historical to novel leads for the treatment of β-globinopathies
Andrieu-Soler, Charlotte
Soler, Eric
[J]. CURRENT OPINION IN HEMATOLOGY, 2020, 27 (03) : 141 - 148
[3] Structural Insights into c-Myc-interacting Zinc Finger Protein-1 (Miz-1) Delineate Domains Required for DNA Scanning and Sequence-specific Binding
Bedard, Mikael
Roy, Vincent
Montagne, Martin
Lavigne, Pierre
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2017, 292 (08) : 3323 - 3340
[4] LONG-RANGE MOTIONAL RESTRICTIONS IN A MULTIDOMAIN ZINC-FINGER PROTEIN FROM ANISOTROPIC TUMBLING
BRUSCHWEILER, R
LIAO, XB
WRIGHT, PE
[J]. SCIENCE, 1995, 268 (5212) : 886 - 889
[5] BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis
Canver, Matthew C.
Smith, Elenoe C.
Sher, Falak
Pinello, Luca
Sanjana, Neville E.
Shalem, Ophir
Chen, Diane D.
Schupp, Patrick G.
Vinjamur, Divya S.
Garcia, Sara P.
Luc, Sidinh
Kurita, Ryo
Nakamura, Yukio
Fujiwara, Yuko
Maeda, Takahiro
Yuan, Guo-Cheng
Zhang, Feng
Orkin, Stuart H.
Bauer, Daniel E.
[J]. NATURE, 2015, 527 (7577) : 192 - +
[6] A POINT MUTATION IN THE A-GAMMA-GLOBIN GENE PROMOTER IN GREEK HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN
COLLINS, FS
METHERALL, JE
YAMAKAWA, M
PAN, J
WEISSMAN, SM
FORGET, BG
[J]. NATURE, 1985, 313 (6000) : 325 - 326
[7] NMRPIPE - A MULTIDIMENSIONAL SPECTRAL PROCESSING SYSTEM BASED ON UNIX PIPES
DELAGLIO, F
GRZESIEK, S
VUISTER, GW
ZHU, G
PFEIFER, J
BAX, A
[J]. JOURNAL OF BIOMOLECULAR NMR, 1995, 6 (03) : 277 - 293
[8] Molecular Dynamics Simulations of Reduced and Oxidized TFIIIA Zinc Fingers Free and Interacting with 5S RNA
Dreab, Ana
Bayse, Craig A.
[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2022, 62 (04) : 903 - 913
[9] Coot:: model-building tools for molecular graphics
Emsley, P
Cowtan, K
[J]. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 : 2126 - 2132
[10] Eom KS, 2016, J MICROBIOL BIOTECHN, V26, P2019

← 1 2 3 4 5 6 7 8 →