PhD student: Single-molecule biophysics of the ubiquitin motor Cdc48/p97

Work Activities
Summary - In this project, you will perform innovative (bio)physics experiments to elucidate the dynamic action of ubiquitin-processing enzymes. The key methodologies are optical tweezers and single-molecule fluorescence. Working in the Tans biophysics lab @ AMOLF Amsterdam, you will visualize how enzymes such as Cdc48/p97 bind, unfold, and translocate unfolded ubiquitin molecules through their central pore, and what role is played by their unique branched topology. These actions are critical, yet have never been reported. The work is embedded in an international team, with other groups specialized in in-vitro biology and biochemistry. Building on very recent breakthroughs in our team, your aim is to elucidate for the first time the dynamic mechanisms that underlie this pivotal function.

Questions – Ubiquitin is central to a broadly important regulatory system within cells, which controls anything from protein degradation to membrane remodeling and DNA replication regulation. Cdc48 performs these tasks by disassembling protein complexes, extracting proteins from membranes, unfolding misfolded proteins, and by delivering proteins to the proteasome. Cdc48 must select target proteins marked with specific polyubiquitin chains, which can exhibit highly diverse ubiquitin linkages, topologies, and biochemical modifications. Despite the key role of Cdc48 and polyubiquitin structural changes in this process, polyubiquitin handling by Cdc48 has not been studied directly. Accessing these dynamics will allow you to address many questions with a unique angle: Does Cdc48 translocate ubiquitin loops and branch points? At which speed, force, and pause-dynamics? How does this dynamics allow Cdc48 to specifically select some ubiquitin chains and not others? Do regulatory proteins steer this process, and the competition with the alternative proteasome pathway? Given the novelty of these fundamental questions in this rapidly expanding field, you will have a unique chance to address them for the first time.

Approach - You will directly follow the unknown dynamics of polyubiquitin processing by Cdc48. This is enabled using optical tweezers combined with single-molecule fluorescence, which detect changes in individual molecules at nanometer and millisecond resolution. Direct collaboration with our partners in Germany provides complementary in-vitro data. This first look may reveal a host of unexpected phenomena. You will develop new experimental schemes, use cutting-edge single-molecule fluorescence and manipulation methods, adapt existing biochemical protocols, analyze the complex temporal data, formulation of new models, and explain your findings in high-level scientific papers.

Qualifications
We have a number of positions available (PhD and PD). We are looking for outstanding experimental physicists or chemists with an interest in single-molecule techniques, ambition to make breakthrough findings, programming skills to handle complex data, and who thrive in a diverse, collaborative, and supportive environment. Excellent verbal and written English skills are essential. You meet the requirements for an MSc-degree to ensure eligibility for a Dutch PhD examination.

Work environment
AMOLF is a part of NWO-I and initiate and performs leading fundamental research on the physics of complex forms of matter, and to create new functional materials, in partnership with academia and industry. The institute is located at Amsterdam Science Park and currently employs about 140 researchers and 80 support employees. www.amolf.nl

Our group - We form a lively and close-knit research group of about 10 PhD students and postdocs, which work together in small teams on various projects in a highly supportive and social atmosphere that extends to the other research groups at the AMOLF institute, which is housed in a modern building in the east of Amsterdam. The Tans group at the AMOLF institute Amsterdam has been at the forefront of studying chaperone-guided protein folding using optical tweezers. This technique allows one to mechanically manipulate individual proteins, and hence follow the movements and folding steps as they fold. We have shown striking sequences of molecular events that underlie chaperone functions, which are invisible with other methods.

https://www.sandertanslab.nl

https://amolf.nl/research-groups/biophysics

Working conditions

• The working atmosphere at the institute is largely determined by young, enthusiastic, mostly foreign employees. Communication is informal and runs through short lines of communication.
• The position is intended as full-time (40 hours / week, 12 months / year) appointment in the service of the Netherlands Foundation of Scientific Research Institutes (NWO-I) for the duration of four years
• The starting salary is 2.781 Euro’s gross per month and a range of employment benefits.
• After successful completion of the PhD research a PhD degree will be granted at Delft University of Technology.
• Several courses are offered, specially developed for PhD-students.
• Funding is available to attend regularly international conferences.
• AMOLF assists any new foreign PhD-student with housing and visa applications and compensates their transport costs and furnishing expenses.

More information?
For further information about the position, please contact

Prof. dr. ir. Sander Tans
tans@amolf.nl
https://www.sandertanslab.nl
Phone: +31-(0)20-754 7100

Application
You can respond to this vacancy online via the button below.

Please annex your:

• Resume;
• Motivation on why you want to join the group (max. 1 page).

It is important to us to know why you want to join our team. Hence, we will only consider your application if it contains your motivation letter.

Applications will be evaluated on a rolling basis and as soon as an excellent match is made, the position will be filled.

Online screening may be part of the selection.

Diversity code
AMOLF is highly committed to an inclusive and diverse work environment: we want to develop talent and creativity by bringing together people from different backgrounds and cultures. We recruit and select on the basis of competencies and talents. We strongly encourage anyone with the right qualifications to apply for the vacancy, regardless of age, gender, origin, sexual orientation or physical ability.

AMOLF has won the NNV Diversity Award 2022, which is awarded every two years by the Netherlands Physical Society for demonstrating the most successful implementation of equality, diversity and inclusion (EDI).

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