LICAMM How do cardiac myosin-binding protein C and titin interact in health and disease?

Cardiac myosin-binding protein C (cMyBP-C) and titin are components of the contractile unit of vertebrate muscle with structural and regulatory roles in the heart. Mutations within both proteins are associated with inherited heart diseases for which there is significant disease burden and no cures. cMyBP-C mutations are a chief cause of hypertrophic cardiomyopathy, which affects ~0.2 % to 0.5% of the population and is the leading cause of sudden onset cardiac arrest in the young [1]. Titin mutations, lead to dilated cardiomyopathy, which has a similar incidence [2]. The molecular mechanisms by which missense mutations in these two proteins lead to disease are largely unknown. Characterisation of the molecular interactions of cMyBP-C with titin, and the structure of titin within the A-band of the sarcomere will aid in our understanding of vertebrate thick filament structure in health and disease.

<p style="text-align:justify">The project will examine how the C-terminal half of cMyBP-C interactions with titin in the sarcomere. A new interaction site of cMyBP-C with titin3,4 has recently been proposed but has not been characterised in molecular detail. This project will use expressed constructs and purified tissue to characterise the interactions between cMyBP-C and titin in vitro and in situ by use of cryo-electron microscopy, modelling, mass spectrometry, and biophysical characterisation. The effect of mutations, which cause heart disease, on these interactions will also be examined.</p> <h5>References</h5> <ol> <li>Semsarian, C., Ingles, J., Maron, M. S. & Maron, B. J. New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy. J. Am. Coll. Cardiol. 65, 1249–1254 (2015).</li> <li>Tharp, C. A., Haywood, M. E., Sbaizero, O., Taylor, M. R. G. & Mestroni, L. The Giant Protein Titin’s Role in Cardiomyopathy: Genetic, Transcriptional, and Post-translational Modifications of TTN and Their Contribution to Cardiac Disease   . Frontiers in Physiology   vol. 10 (2019).</li> <li>Bennett, P., Rees, M. & Gautel, M. The Axial Alignment of Titin on the Muscle Thick Filament Supports Its Role as a Molecular Ruler. J. Mol. Biol. 432, 4815–4829 (2020).</li> <li>Tonino, P., Kiss, B., Gohlke, J., Smith  III, J. E. & Granzier, H. Fine mapping titin’s C-zone: Matching cardiac myosin-binding protein C stripes with titin’s super-repeats. J. Mol. Cell. Cardiol. 133, 47–56 (2019).</li> </ol>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. You should complete an <a href="https://medicinehealth.leeds.ac.uk/faculty-graduate-school/doc/apply-2">online application form</a> and attach the following documentation to support your application. </p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks (or marks so far if still studying)</li> <li>Evidence that you meet the programme’s minimum English language requirements (if applicable, see requirement below)</li> <li>Evidence of funding to support your studies</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Medicine, Health & Human Disease as your planned programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject area is desirable but not essential.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

<p>For further information please contact the Faculty Graduate School<br /> e:<a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p>