Master Thesis in Structural Biology – Djinovic Lab

22/01/2019

Structure of ZASP/α-actinin complex: deep insight into muscle Z-disk structure and function

Movement of animals is carried out by striated muscle, the contractile unit of which is the sarcomere. The Z-disks are complex sub-compartments that define the lateral boundaries between two adjacent sarcomeres. α-Actinin is its major component and plays a key role in cross-linking actin and titin filaments into the molecular machinery that is required for muscle contraction (Ribeiro et al., Cell 2014). There are several proteins know to interact with α-actinin and use it as a scaffold and/or regulate and fine tune its function. Among of these Z-band alternatively spliced PDZ-motif protein (ZASP) was suggested to play critical role in maintenance of Z-disc structure as ZASP knock-out mice are embryonic lethal and die from functional failure in multiple striated muscle types displaying disorganized and fragmented Z-disks (Zhou et al., 2001). In addition mutations in ZASP are involved in several muscle diseases. To understand how ZASP binds to α-actinin and regulates its activity we aim at obtaining 3D structure of ZASP/α-actinin complex using a combination of complementary approaches - X-ray crystallography and SAXS, together with biochemical and biophysical methods to characterize this interaction. In the next step, we aim to uncover the role of ZASP in formation of higher order Z-disk complexes and development of muscle diseases focusing on characterization of ternary and quaternary complexes formed by ZASP, α-actinin and their interaction partners e.g. titin, FATZ.

We are looking for a highly motivated student to join this interesting and highly challenging project. Requirements: Studies of Molecular Biology, Biochemistry, Cell Biology, Chemistry or related field. Students interested in protein structure and function, please send a CV anletter of motivation to kristina.djinovic@univie.ac.at and julius.kostan [AT] univie.ac [DOT] at.Duration of thesis: 10 months, salary: 440 € per month. Beginning: immediately.


Kristina Djinovic Carugo 

Department of Structural and Computational Biology

Max F. Perutz Laboratories

University of Vienna

Campus Vienna Biocenter 5, A-1030 Vienna

kristina.djinovic [AT] univie.ac [DOT] at

https://www.mfpl.ac.at/groups/mfpl-group/group-info/djinovic.html


Relevant publications:

Ribeiro et al, (2014) The structure and regulation of human muscle α-actinin. Cell 159: 1447-60Zhou et al, (2001) Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy. J Cell Biol, 155: 605-612