Molecular basis of TGFß/BMP signalling in cardiovascular diseases
I am interested in how protein-protein recognition regulates TGFb family signalling, how defects in such interaction cause cardiovascular disease and how to employ such knowledge for therapeutic purposes.
There are over 30 TGFb family ligands in humans. Their signals are mediated by forming a signalling complex with one of the 7 type I receptors and one of the 5 type II receptors. These signalling complexes are further regulated by specific interactions with prodomain, co-receptors and ligand traps. The complexity of such protein-protein interaction network fine-tunes the outcome of TGFb family signalling, contributing to the homeostasis of many essential biological processes, such as vascular quiescence, wound healing and immune system.
The current focus of the group is on BMP9(10):ALK1:BMPRII pathways on vascular endothelial cells and their interactions with co-receptor endoglin (ENG). BMP9 and BMP10 form the major circulating BMP activity, signalling particular potently in vascular endothelial cells with EC50 in the pg/ml range. ALK1 is the type I receptor highly expressed on endothelial cells and specific for BMP9 and BMP10, whereas BMPRII is the ubiquitous type II receptor for over 15 BMP ligands.
Human genetics strongly support the importance of this pathway in cardiovascular diseases. Mutations in ALK1 and ENG cause Hereditary Haemorrhagic Telangiectasia (HHT), an autosomal dominant vascular disorder where patients have weak blood vessels in internal organs which can cause unexpected life-threatening bleeding. Mutations in BMPR2, GDF2 (encoding BMP9), BMP10, ALK1 and ENG have been found in patients with pulmonary arterial hypertension (PAH). These patients have elevated blood pressure in pulmonary circulation due to the remodelling of pulmonary arteries, eventually result in right ventricular hypertrophy and death due to heart failure.
Our research on the molecular basis of endothelial BMP signalling pathways has led to a number of novel findings. We reported that BMP9 is regulated by redox-dependent proteolysis, prodomain does not confer latency to BMP10, soluble ENG does not inhibit but modifies BMP9 and 10 signalling in vascular endothelial cells, and the molecular recognition of these ALK1-ligands signalling in endothelial cells. We also show that loss of endogenous BMP9 leads to lung vascular leak in vivo, and have developed BMP9 variants that maintain endothelial protective function but lack the bone-forming activity. Such variants are currently under drug development programme at our spin-out company Morphogen-IX, which I am a co-founder with Prof. Nick Morrell and Dr Paul Upton.
We employ multidisciplinary approaches including protein chemistry, protein engineering, structural biology, biophysical and cell biology assays. We routinely use mammalian cell lines as well as control and patient-derived primary cells for signalling and functional assays.
Li W, Long L, Yang X, Tong Z, Southwood M, King R, Caruso P, Upton PD, Yang P, Bocobo GA, Nikolic I, Higuera A, Salmon RM, Jiang H, Lodge KM, Hoenderdos K, Baron RM, Yu PB,Condliffe AM, Summers C, Nourshargh S, Chilvers ER, Morrell NW. (2020) Circulating BMP9 Protects the Pulmonary Endothelium During Inflammation-induced Lung Injury in Mice. Am J Respir Crit Care Med. doi: 10.1164/rccm.202005-1761OC. Online ahead of print.
Salmon RM, Guo J, Wood JH, Tong Z, Lawera, A, Yu M, Beech JS, Grainger DJ, Reckless, J, Morrell NW and Li W (2020) Molecular basis of ALK1-mediated signaling by BMP9/BMP10 and their prodomain bound forms.Nature Communications. 11, Article number: 1621
Vacca M, ... Li W, Kostrzewski T, Leeming DJ, Ratziu, V, Allison MED, Anstee QM, Griffin JL, Oakley F and Vidal-Puig A (2020) Bone Morphogenetic protein 8B (BMP8B) tunes TGFb/BMP signaling in liver disease contributing to non-alcoholic steatohepatitis. Nature Metabolism, 2, 514-531.
Lawera A, Tong Z, Thorikay M, Redgrave RE, Cai J, van Dinther M, Morrell NW, Afink GB, Charnock-Jones DS, Arthur HM, ten Dijke P and Li W (2019) Role of Soluble Endoglin in BMP9 Signaling. Natl. Acad. Sci. USA 116: 17800-08.
Wood JH, Guo JX, Morrell NW and Li W (2019) Advances in the molecular regulation of endothelial BMP9 signalling complexes and implication for cardiovascular disease. Biochemical Society Transactions, 47:779-91.
Graf S, Haimel M, Bleda M, Hadinnapola C, Southgate L, Li W, et al. (2018) Identification of rare sequence variation underlying heritable pulmonary arterial hypertension Nat Communication, 9: 1416.
Li W* and Huntington JA* (2012) Crystal structures of protease nexin-1 in complex with heparin and thrombin suggest a two-step recognition mechanism Blood. 120: 459-67. (*Joint corresponding author)
Yamasaki M, Li W, Johnson DJD and Huntington JA (2008) Crystal structure of a stable dimer reveals the molecular basis of serpin polymerisation. Nature, 455, 1255-8.
Li W, Adams TE, Nangalia J, Esmon CT and Huntington JA (2008) Molecular basis of thrombin recognition by protein C inhibitor revealed by the 1.6Å structure of the heparin-bridged complex. Natl. Acad. Sci. USA, 105, 4661-6.
Li W, Johnson, DJD, Esmon, CT, Huntington, JA (2004) Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin. Nature Structural & Molecular Biology. 11, 857-62.