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

ABSTRACT:

Background

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).

Results

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 cryst

SUBMITTER: Hnizda A 

PROVIDER: S-EPMC5070119 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature