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Instruments / Technical Area	Publication Details	Published
B21-High Throughput SAXS	Mammalian tolloid proteinases: role in growth factor signalling Helen Troilo , Christopher P. Bayley , Anne L. Barrett , Michael P. Lockhart-Cairns , Thomas A. Jowitt , Clair Baldock Febs Letters 590, 2398 - 2407 DOI: 10.1002/1873-3468.12287 Open Access Show Abstract ▼ Abstract: Tolloid proteinases are essential for tissue patterning and extracellular matrix assembly. The members of the family differ in their substrate specificity and activity, despite sharing similar domain organization. The mechanisms underlying substrate specificity and activity are complex, with variation between family members, and depend on both multimerization and substrate interaction. In addition, enhancers, such as Twisted gastrulation (Tsg), promote cleavage of tolloid substrate, chordin, to regulate growth factor signalling. Although Tsg and mammalian tolloid (mTLD) are involved in chordin cleavage, no interaction has been detected between them, suggesting Tsg induces a change in chordin to increase susceptibility to cleavage. All members of the tolloid family bind the N terminus of latent TGFβ-binding protein-1, providing support for their role in TGFβ signalling.	Aug 2016
I22-Small angle scattering & Diffraction	Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway Helen Troilo , Anne L. Barrett , Alexandra V. Zuk , Michael P. Lockhart-Cairns , Alexander P. Wohl , Christopher Bayley , Rana Dajani , Richard Tunnicliffe , Lewis Green , Thomas A. Jowitt , Gerhard Sengle , Clair Baldock Matrix Biology DOI: 10.1016/j.matbio.2016.01.019 PMID: 26829466 Diamond Proposal Number(s): [6457] Open Access Show Abstract ▼ Abstract: Twisted gastrulation (Tsg) and chordin are secreted glycoproteins that function together as BMP (Bone Morphogenetic Protein) antagonists to regulate BMP growth factor signalling. Chordin binds to BMPs, preventing them from interacting with their receptors and Tsg is known to strengthen this inhibitory complex. Tsg also acts as a BMP agonist by promoting cleavage of chordin by tolloid-family proteinases. Here we explore the structural mechanism through which Tsg exerts this dual activity. We have characterized the nanoscale structure of human Tsg using in-solution biomolecular analysis and show that Tsg is a globular monomer with a flattened cross shape. Tsg has a high proportion of N-linked glycans, in relation to its molecular weight, which supports a role in solubilising BMPs. Tsg binds with high affinity to the C-terminal region of chordin and was also able to inhibit BMP-7 signalling directly but did not have an effect on BMP-4 signalling. Although both Tsg and mammalian tolloid are involved in chordin cleavage, no interaction could be detected between them using surface plasmon resonance. Together these data suggest that Tsg functions as a BMP-agonist by inducing conformational change in chordin making it more susceptible to tolloid cleavage and as a BMP-antagonist either independently or via a chordin-mediated mechanism. Following single cleavage of chordin by tolloids, Tsg continues to strengthen the inhibitory complex, supporting a role for partially cleaved chordin in BMP regulation.	Jan 2016
I22-Small angle scattering & Diffraction	Heterogeneity of collagen VI microfibrils: structural analysis of non-collagenous regions Tobias Maaß , Christopher P Bayley , Matthias Mörgelin , Sandra Lettmann , Paolo Bonaldo , Mats Paulsson , Clair Baldock , Raimund Wagener Journal Of Biological Chemistry DOI: 10.1074/jbc.M115.705160 Open Access Show Abstract ▼ Abstract: Collagen VI, a collagen with uncharacteristically large N- and C-terminal non-collagenous regions, forms a distinct microfibrillar network in most connective tissues. It was long considered to consist of three genetically distinct α chains (α1, α2 and α3). Intracellularly heterotrimeric molecules associate to form dimers and tetramers, which are then secreted and assembled to microfibrils. The identification of three novel long collagen VI α chains α4, α5, and α6 led to the question if and how these may substitute for the long α3 chain in collagen VI assembly. Here we studied structural features of the novel long chains, and analyzed the assembly of these into tetramers and microfibrils. N- and C-terminal globular regions of collagen VI were recombinantly expressed and studied by SAXS. Ab initio models of the N-terminal globular regions of the α4, α5 and α6 chains showed a C-shaped structure similar to that found for the α3 chain. Single particle EM nanostructure of the N-terminal globular region of the α4 chain confirmed the C-shaped structure revealed by SAXS. Immuno EM of collagen VI extracted from tissue revealed that like the α3 chain the novel long chains assemble to homotetramers that are incorporated into mixed microfibrils. Moreover, SAXS models of the C-terminal globular regions of the α1, α2, α4, and α6 chains were generated. Interestingly, the α1, α2 and α4 C-terminal globular regions dimerize. These self-interactions may play a role in tetramer formation.	Jan 2016

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