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Adopting orphan pumps: Structural and functional characterization of P5-ATPases

Project description

Investigating the function of P5 ATPase pumps in our cells

P-type ATP synthases or ATPases are a large group of evolutionarily related ion and lipid pumps that are found in bacteria, archaea and eukaryotes. Prominent examples include sodium–potassium and calcium pumps. Little is known about P5 ATPases, which are found only in eukaryotes and whose malfunctions have been linked to severe neurological diseases. The EU-funded hyP5 project plans to find out more about their substrate specificity and structure as well as their cellular interaction network using different methods, including native mass spectroscopy, cryo-electron microscopy and X-ray crystallography. The project's findings could help unravel the molecular mechanisms of neurodegenerative and cognitive disorders and guide the development of new drugs.

Objective

P5-ATPases are conserved in all eukaryotes and malfunctions in human are associated with severe neurological diseases, such as familial early-onset parkinsonism and autism/language disorders, and with phenotypical traits in yeasts. They belong to the P-type ATPase superfamily, which encompass a range of essential membrane transporters for ions and lipids. Ion pumps such as Na,K-ATPase and Ca2+-ATPase have been studied in great detail during the last decades. However, astonishingly little is known about the P5-ATPases and their actual function, despite their physiological importance in all eukaryotes.
The current proposal focuses on substrate identification and structural characterization of P5-ATPases, as well as investigations of their cellular interaction network. Human P5-ATPases (ATP13A1 through 5, ATP13A2 also known as PARK9) and the yeast orthologues Spf1p and Ypk9p will be subjects of this study. Target proteins will be expressed in their native host (yeast or HEK cells) and subsequently purified and used for activity assays, structural studies, and identification of interaction partners. Native mass spectrometry will identify bound substrates and cofactors, and activity studies will elucidate structure-function relationships. 3D-structures obtained by single-particle cryo-electron microscopy (cryo-EM) and/or X-ray crystallography will reveal catalytic mechanisms and mutational effects. Structural and functional characterization of P5-ATPases can therefore serve as a basis for understanding molecular mechanisms of e.g. neurodegenerative and cognitive disorders and guide novel strategies in disease treatments and drug discovery.
Using my profound experience from my PhD with crystallography of biotechnologically relevant proteins, I wish to pursue a postdoc focused on membrane proteins with a strong potential in molecular medicine and to expand my knowledge of methods in structural biology and molecular cell biology, in particular cryo-EM.

Coordinator

AARHUS UNIVERSITET
Net EU contribution
€ 219 312,00
Address
NORDRE RINGGADE 1
8000 Aarhus C
Denmark

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Region
Danmark Midtjylland Østjylland
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 219 312,00