Oligomeric interface modulation causes misregulation of purine 5'-nucleotidase in relapsed leukemia

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F16%3A00466505" target="_blank" >RIV/68378050:_____/16:00466505 - isvavai.cz</a>

Alternative codes found

RIV/61388971:_____/16:00466505 RIV/61388963:_____/16:00466505

Result on the web

<a href="http://bmcbiol.biomedcentral.com/articles/10.1186/s12915-016-0313-y" target="_blank" >http://bmcbiol.biomedcentral.com/articles/10.1186/s12915-016-0313-y</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s12915-016-0313-y" target="_blank" >10.1186/s12915-016-0313-y</a>

Result language

angličtina

Original language name

Oligomeric interface modulation causes misregulation of purine 5'-nucleotidase in relapsed leukemia

Original language description

Relapsed acute lymphoblastic leukemia (ALL) is one of the main causes of mortality in childhood malignancies. Previous genetic studies demonstrated that chemoresistant ALL is driven by activating mutations in NT5C2, the gene encoding cytosolic 5'-nucleotidase (cN-II). However, molecular mechanisms underlying this hyperactivation are still unknown. Here, we present kinetic and structural properties of cN-II variants that represent 75 % of mutated alleles in patients who experience relapsed ALL (R367Q, R238W and L375F). Enzyme kinetics measurements revealed that the mutants are consitutively active without need for allosteric activators. This shows that hyperactivity is not caused by a direct catalytic effect but rather by misregulation of cN-II. X-ray crystallography combined with mass spectrometry-based techniques demonstrated that this misregulation is driven by structural modulation of the oligomeric interface within the cN-II homotetrameric assembly. These specific conformational changes are shared between the studied variants, despite the relatively random spatial distribution of the mutations. These findings define a common molecular mechanism for cN-II hyperactivity, which provides a solid basis for targeted therapy of leukemia. Our study highlights the cN-II oligomerization interface as an attractive pharmacological target.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

CE - Biochemistry

OECD FORD branch

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Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

BMC BIOLOGY

ISSN

1741-7007

e-ISSN

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Volume of the periodical

14

Issue of the periodical within the volume

Oct 19

Country of publishing house

GB - UNITED KINGDOM

Number of pages

16

Pages from-to

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UT code for WoS article

000385884200001

EID of the result in the Scopus database

2-s2.0-84992162172