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(BBSRC DTP) Structure and functional study to probe the mechanism of BMP regulation by the chordin family


Project Description

Bone morphogenetic proteins (BMPs) are key signalling molecules in embryonic development and adult tissue homeostasis, and are heavily regulated in the extracellular matrix. Extracellular regulation of BMPs is essential for correct development and is of therapeutic interest in relation to a broad range of pathologies including cancer, vascular disease and osteoporosis. Extracellular glycoproteins form inhibitory complexes with BMPs, thereby preventing receptor activation but the molecular details of these complexes remain unclear. The Chordin protein family of BMP antagonists bind BMPs in the matrix thereby physically preventing their association with BMP receptors on the cell surface to inhibit BMP signalling. A major focus to date has been on understanding the events downstream of receptor signalling, yet the mechanisms for regulating growth factor availability prior to receptor engagement remain to be elucidated. Another BMP regulator, Twisted gastrulation (Tsg), further modulates BMP inhibition by the chordin family and it is hypothesised that this is achieved through formation of a ternary regulatory complex. However, the mechanism of inhibition by the Chordin family and their modulation by Tsg is not fully understood. Chordin-like 2 (CHRDL2) is a member of the chordin family that binds BMPs to inhibit BMP signalling and the formation of a ternary CHRDL2-Tsg-BMP-2 complex further enhances BMP inhibition. CHRDL2 remains largely uncharacterised but could be a vital tool in understanding the details of BMP inhibition by members of the Chordin family.

The aim of this project therefore is to purify the CHRDL2-Tsg-BMP-2 ternary complex for structural analysis using small angle X-ray scattering and cryoEM which will provide a detailed structural understanding of the interactions of CHRDL2 with BMPs and Tsg in the ternary complex. This would provide the first model for the binding of a Chordin family member to Tsg and BMP within the regulatory ternary complex. The structural model generated will allow us to test the mechanism of action of chordin family members and Tsg on BMP signalling in vivo by introducing structure-derived mutations into homologous fly proteins to determine their effects on BMP signalling in the Drosophila embryo. Together this multidisciplinary approach will combine biochemistry, structural biology and developmental biology to address fundamental questions in biology.

http://www.wellcome-matrix.org/research_groups/clair-baldock.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Lockhart-Cairns MP, Lim KTW, Zuk A, Godwin ARF, Cain SA, Sengle G, Baldock C. Internal cleavage and synergy with twisted gastrulation enhance BMP inhibition by BMPER. Matrix Biol. 2018 doi:10.1016/j.matbio.2018.08.006.

Troilo H, Barrett AL, Zuk AV, Lockhart-Cairns MP, Wohl AP, Bayley CP, Dajani R, Tunnicliffe RB, Green L, Jowitt TA, Sengle G, Baldock C. Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway. Matrix Biol. 2016 55:49-62.

Ramsay EP, Collins RF, Owens TW, Siebert CA, Jones RPO, Wang T, Roseman AM, Baldock C. Structural analysis of X-linked retinoschisis mutations reveals distinct classes which differentially effect retinoschisin function. Hum Mol Genet. 2016 25:5311-5320.

Winstanley J, Sawala A, Baldock C, Ashe HL. Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation. Elife. 2015 4:e05508.

Troilo H, Zuk AV, Tunnicliffe RB, Wohl AP, Berry R, Collins RF, Jowitt TA, Sengle G, Baldock C. Nanoscale structure of the BMP antagonist chordin supports cooperative BMP binding. Proc Natl Acad Sci U S A. 2014 111:13063-8.

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