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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.

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

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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