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Aggregation and retention of human urokinase type plasminogen activator in the yeast endoplasmic reticulum.


ABSTRACT: BACKGROUND:Secretion of recombinant proteins in yeast can be affected by their improper folding in the endoplasmic reticulum and subsequent elimination of the misfolded molecules via the endoplasmic reticulum associated protein degradation pathway. Recombinant proteins can also be degraded by the vacuolar protease complex. Human urokinase type plasminogen activator (uPA) is poorly secreted by yeast but the mechanisms interfering with its secretion are largely unknown. RESULTS:We show that in Hansenula polymorpha overexpression worsens uPA secretion and stimulates its intracellular aggregation. The absence of the Golgi modifications in accumulated uPA suggests that aggregation occurs within the endoplasmic reticulum. Deletion analysis has shown that the N-terminal domains were responsible for poor uPA secretion and propensity to aggregate. Mutation abolishing N-glycosylation decreased the efficiency of uPA secretion and increased its aggregation degree. Retention of uPA in the endoplasmic reticulum stimulates its aggregation. CONCLUSIONS:The data obtained demonstrate that defect of uPA secretion in yeast is related to its retention in the endoplasmic reticulum. Accumulation of uPA within the endoplasmic reticulum disturbs its proper folding and leads to formation of high molecular weight aggregates.

SUBMITTER: Agaphonov MO 

PROVIDER: S-EPMC130179 | biostudies-literature | 2002 Oct

REPOSITORIES: biostudies-literature

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Aggregation and retention of human urokinase type plasminogen activator in the yeast endoplasmic reticulum.

Agaphonov Michael O MO   Romanova Nina V NV   Trushkina Polina M PM   Smirnov Vladimir N VN   Ter-Avanesyan Michael D MD  

BMC molecular biology 20021007


<h4>Background</h4>Secretion of recombinant proteins in yeast can be affected by their improper folding in the endoplasmic reticulum and subsequent elimination of the misfolded molecules via the endoplasmic reticulum associated protein degradation pathway. Recombinant proteins can also be degraded by the vacuolar protease complex. Human urokinase type plasminogen activator (uPA) is poorly secreted by yeast but the mechanisms interfering with its secretion are largely unknown.<h4>Results</h4>We s  ...[more]

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