Designer TGFβ Superfamily Ligands with Diversified Functionality

被引：33

作者：

Allendorph, George P. ^{[1
,2
]}

Read, Jessica D. ^{[3
]}

Kawakami, Yasuhiko ^{[4
,5
]}

Kelber, Jonathan A. ^{[3
]}

Isaacs, Michael J. ^{[1
]}

Choe, Senyon ^{[1
,2
]}

机构：

[1] Gachon Univ Med & Sci, Joint Ctr Biosci, Lee Gil Ya Canc & Diabet Inst, Inchon, South Korea

[2] Salk Inst Biol Studies, Struct Biol Lab, La Jolla, CA 92037 USA

[3] Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, La Jolla, CA 92037 USA

[4] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN USA

[5] Univ Minnesota, Stem Cell Inst, Minneapolis, MN USA

来源：

PLOS ONE | 2011年 / 6卷 / 11期

关键词：

EMBRYONIC STEM-CELLS; ACTIVIN-A; BINDING-SPECIFICITY; CRYSTAL-STRUCTURE; GROWTH-FACTORS; RECEPTORS; DIFFERENTIATION; COMPLEX; PURIFICATION; KINASE;

D O I：

10.1371/journal.pone.0026402

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Transforming Growth Factor - beta (TGF beta) superfamily ligands, including Activins, Growth and Differentiation Factors (GDFs), and Bone Morphogenetic Proteins (BMPs), are excellent targets for protein-based therapeutics because of their pervasiveness in numerous developmental and cellular processes. We developed a strategy termed RASCH (Random Assembly of Segmental Chimera and Heteromer), to engineer chemically-refoldable TGF beta superfamily ligands with unique signaling properties. One of these engineered ligands, AB208, created from Activin-beta A and BMP-2 sequences, exhibits the refolding characteristics of BMP-2 while possessing Activin-like signaling attributes. Further, we find several additional ligands, AB204, AB211, and AB215, which initiate the intracellular Smad1-mediated signaling pathways more strongly than BMP-2 but show no sensitivity to the natural BMP antagonist Noggin unlike natural BMP-2. In another design, incorporation of a short N-terminal segment from BMP-2 was sufficient to enable chemical refolding of BMP-9, without which was never produced nor refolded. Our studies show that the RASCH strategy enables us to expand the functional repertoire of TGF beta superfamily ligands through development of novel chimeric TGF beta ligands with diverse biological and clinical values.

引用

页数：12

共 53 条

[1] BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors [J].

Allendorph, George P. ;

Isaacs, Michael J. ;

Kawakami, Yasuhiko ;

Belmonte, Juan Carlos Izpisua ;

Choe, Senyon .

BIOCHEMISTRY, 2007, 46 (43) :12238-12247

[2] Structure of the ternary signaling complex of a TGF-β superfamily member [J].

Allendorph, George P. ;

Vale, Wylie W. ;

Choe, Senyon .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (20) :7643-7648

[3]

Attisano Liliana, 1996, Cytokine and Growth Factor Reviews, V7, P327, DOI 10.1016/S1359-6101(96)00042-1

[4] Recombination of protein fragments: A promising approach toward engineering proteins with novel nanomechanical properties [J].

Balamurali, M. M. ;

Sharma, Deepak ;

Chang, Anderson ;

Khor, Dingyue ;

Chu, Ricky ;

Li, Hongbin .

PROTEIN SCIENCE, 2008, 17 (10) :1815-1826

[5] Activin A maintains pluripotency of human embryonic stem cells in the absence of feeder layers [J].

Beattie, GM ;

Lopez, AD ;

Bucay, N ;

Hinton, A ;

Firpo, MT ;

King, CC ;

Hayek, A .

STEM CELLS, 2005, 23 (04) :489-495

[6] Bone morphogenetic protein 9:: A potent modulator of cartilage development in vitro [J].

Blunk, T ;

Sieminski, AL ;

Appel, B ;

Croft, C ;

Courter, DL ;

Chieh, JJ ;

Goepferich, A ;

Khurana, JS ;

Gooch, KJ .

GROWTH FACTORS, 2003, 21 (02) :71-77

[7] Myostatin as a therapeutic target for musculoskeletal disease [J].

Bradley, L. ;

Yaworsky, P. J. ;

Walsh, F. S. .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2008, 65 (14) :2119-2124

[8] Crystal structure of BMP-9 and functional interactions with pro-region and receptors [J].

Brown, MA ;

Zhao, QH ;

Baker, KA ;

Naik, C ;

Chen, C ;

Pukac, L ;

Singh, M ;

Tsareva, T ;

Parice, Y ;

Mahoney, A ;

Roschke, V ;

Sanyal, I ;

Choe, S .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (26) :25111-25118

[9] A role for BMP heterodimers in roof plate-mediated repulsion of commissural axons [J].

Butler, SJ ;

Dodd, J .

NEURON, 2003, 38 (03) :389-401

[10] An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis [J].

Chen, C ;

Grzegorzewski, KJ ;

Barash, S ;

Zhao, QH ;

Schneider, H ;

Singh, M ;

Pukac, L ;

Bell, AC ;

Duan, R ;

Coleman, T ;

Duttaroy, A ;

Cheng, S ;

Hirsch, J ;

Zhang, LY ;

Lazard, Y ;

Fischer, C ;

Barber, MC ;

Ma, ZD ;

Zhang, YQ ;

Reavey, P ;

Zhong, LL ;

Teng, BQ ;

Sanyal, I ;

Ruben, SM ;

Blondel, O ;

Birse, CE .

NATURE BIOTECHNOLOGY, 2003, 21 (03) :294-301

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