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NaKStruc SIGNED

Structural studies of Na,K-ATPase isoforms and mutants

Total Cost €

0

EC-Contrib. €

0

Partnership

0

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 NaKStruc project word cloud

Explore the words cloud of the NaKStruc project. It provides you a very rough idea of what is the project "NaKStruc" about.

complexes    motor    housekeeping    alternating    ions    reactions    structure    voltage    neural    pharmacological    mutations    yeast    health    elevations       body    cardiac    astrocytes    effect    dark    steroids    cryo    partial    structural    cycle    lay    subsequently    atpase    details       microscopy    physiology    attributed    hence    crystallography    isoform    drugs    dependence    beta    childhhod    ray    causing    muscle    na    inhibited    alpha    reaction    isoforms    inactivation    neuronal    exhibit    neurological    molecular    e815k    transient    heart    extracellular    affinity    primary    significantly    hemiplegia    keep    d801n    subunit    ciliary    pump    expressed    heterooligomer    selectively    diseases    cognitive    leaving    physiological    electron    glaucoma    drug    pastoris    lower    purified    root    disorder    elusive    resting    treatment    foundation    regulators    severe    inactive    remained    pichia    differences    disease    inactivate    gap    steeper   

Project "NaKStruc" data sheet

The following table provides information about the project.

Coordinator
AARHUS UNIVERSITET 

Organization address
address: NORDRE RINGGADE 1
city: AARHUS C
postcode: 8000
website: www.au.dk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Denmark [DK]
 Total cost 200˙194 €
 EC max contribution 200˙194 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2017
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2018
 Duration (year-month-day) from 2018-06-01   to  2020-05-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    AARHUS UNIVERSITET DK (AARHUS C) coordinator 200˙194.00

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 Project objective

Isoform complexes of Na,K-ATPase , an αβ-heterooligomer, have recently been identified as crucial regulators of muscle and neural physiology and were furthermore identified as the primary cause of neurological diseases. Of particular interest are α2β2 & α2β3, which are expressed in muscle and astrocytes (α2β2) and the ciliary body (α2β3). Both exhibit a significantly lower affinity for K-ions and a steeper voltage dependence than the housekeeping α1β1 complex. These features keep α2-isoforms inactive at resting conditions but allow to respond to transient elevations of extracellular K after muscle and neuronal activity. Moreover, both complexes can be selectively inhibited by cardiac steroids, making them promising drug targets for the treatment of heart failure (α2β2) and glaucoma (α2β3). Differences in affinity for K and cardiac steroids were attributed to the β-subunit recently, yet the root cause and molecular details remained elusive. Hence, I propose to investigate the structure of α2-isoforms purified from the yeast Pichia pastoris by x-ray crystallography and cryo electron microscopy. In addition to its physiological and pharmacological role mutations of Na,K-ATPase cause severe neurological diseases, e.g. Alternating Hemiplegia of Childhhod. Disease mutations typically inactivate the Na-pump causing severe motor and cognitive disorder. However, the effects of mutations on the ATPase’s reaction cycle have not been investigated in detail, leaving the cause of inactivation in the dark. Part two of the proposal addresses this gap of knowledge. The two most common mutations E815K and D801N will be expressed in P. pastoris and the effect of mutations on partial reactions of the Na,K-ATPase’s reaction cycle will be investigated and subsequently, structural studies will be carried out. This work will promote our understanding of Na,K-ATPase in health and disease and lay the foundation for the development of new drugs.

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