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Post-transcriptional and translational control of type I collagen trimerisation: a combined computational and experimental approach


Project Description

Type I collagen is the major structural component of human and vertebrate animal tissues with normal or abnormal function determined by intracellular hetero- versus homo-trimerisation. Arrays of trimeric collagen molecules form string-like fibrils that provide tissues with tensile strength, elasticity and rigidity in combination with non-collagenous and inorganic tissue components. The collagen molecule trimer is normally formed from two different gene products to form (α1)2(α2)1 heterotrimers, but homotrimers can readily form when the α2 chain is absent. Heterotrimeric collagen appears particularly suited to meet the specific biomechanical demands placed on bone, skin, tendon and cardiovascular tissues whilst aberrant synthesis of homotrimeric type I collagen can disrupt normal tissue homeostasis. The mechanism behind the preferential synthesis of heterotrimers, or aberrant synthesis of homotrimers, is unknown but may related to a more favourable arrangement of stabilising residues in the heterotrimer, or tight control of the relative amounts and localisation of each contributing mRNA.

The aim of this project is to determine conditions that favour heterotrimeric or homotrimeric assembly of type I collagen using cell culture treatments, RNA and protein imaging and computer-based molecular dynamics simulations. The first objective will involve manipulating the ratio of the mRNAs coding for type I collagen, utilising cells in which the coordinated transcriptional regulation of the type I collagen genes is uncoupled. qPCR and metabolic labelling will be utilised to measure the resulting ratios of each of the type I collagen mRNAs and newly-synthesised polypeptide chains. In the second objective the subcellular localisation of the type I collagen mRNAs will be disrupted using inhibitors to specific cytoskeletal components. RNA localisation is an emerging mechanism for post-transcriptional regulation and the localised control of protein synthesis and has the potential to strongly influence type I collagen trimerisation. The third objective will utilise the known crystal structure of the C-terminal trimerisation domain of type I procollagen in powerful molecular dynamics simulations to determine the influence of key residues, redox and ionic conditions in type I collagen trimerisation.

This project provides a unique opportunity to combine laboratory based experiments with in silico studies of protein structure to understand the key steps in the assembly of this essential structural component of human and animal tissues. You will learn cutting edge microscopy and atomistic modelling techniques across two multi-disciplinary training centres, as an essential grounding for future biomedical research and development, as well as key transferable skills for business.

[[How to apply]
Applications should be made by emailing with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.

In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to . A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Identification and Characterization of Canine Ligament Progenitor Cells and Their Extracellular Matrix Niche.” J Proteome Res 18(3): 1328-1339. (2019).

Variations during ageing in the three-dimensional anatomical arrangement of fascicles within the equine superficial digital flexor tendon.” Eur Cell Mater 35: 87-102. (2018)

Cross-species gene modules emerge from a systems biology approach to osteoarthritis.” NPJ Syst Biol Appl 3: 13 (2017).

Matrix metalloproteinase 14 is required for fibrous tissue expansion.” eLife. 4: e09345 (2015).

Stepwise proteolytic activation of type I procollagen to collagen within the secretory pathway of tendon fibroblasts in situ.” Biochem J 441(2): 707-717. (2012).

Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis.” Nature Commun 9:256. (2018)

The aldehyde dehydrogenase AldA contributes to the hypochlorite defense and is redox-controlled by protein S-bacillithiolation in Staphylococcus aureus” Redox Biol 15:557-568 (2018)

A proton relay enhances H2O2 sensitivity of GAPDH to facilitate metabolic adaptation.” Nat Chem Biol 11:156-63 (2015)

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes. Proc Natl Acad Sci U S A. 111:E3177-86 (2014)

Live Imaging of Cell Invasion Using a Multicellular Spheroid Model and Light-Sheet Microscopy” Adv Exp Med Biol 1035:155-161 (2017)

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