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Publication
Reduced Stability and pH-Dependent Activity of a Common Obesity-Linked PCSK1
Polymorphism, N221D.
Authors Jarvela TS, Shakya M, Bachor T, White A, Low MJ, Lindberg I
Submitted By Submitted Externally on 4/13/2020
Status Published
Journal Endocrinology
Year 2019
Date Published 11/1/2019
Volume : Pages 160 : 2630 - 2645
PubMed Reference 31504391
Abstract Common mutations in the human prohormone convertase (PC)1/3 gene (PCKSI) are
linked to increased risk of obesity. Previous work has shown that the rs6232
single-nucleotide polymorphism (N221D) results in slightly decreased activity,
although whether this decrease underlies obesity risk is not clear. We observed
significantly decreased activity of the N221D PC1/3 enzyme at the pH of the
trans-Golgi network; at this pH, the mutant enzyme was less stable than
wild-type enzyme. Recombinant N221D PC1/3 also showed enhanced susceptibility to
heat stress. Enhanced susceptibility to tunicamycin-induced endoplasmic
reticulum stress was observed in AtT-20/PC2 cell clones in which murine PC1/3
was replaced by human N221D PC1/3, as compared with wild-type human PC1/3.
However, N221D PC1/3-expressing AtT-20/PC2 clones processed proopiomelanocortin
to a-MSH similarly to wild-type PC1/3. We also generated a CRISPR-edited mouse
line expressing the N221D mutation in the PCKSI gene. When homozygous N221D mice
were fed either a standard or a high-fat diet, we found no increase in body
weight compared with their wild-type sibling controls. Sexual dimorphism was
observed in pituitary ACTH for both genotypes, with females exhibiting lower
levels of pituitary ACTH. In contrast, hypothalamic a-MSH content for both
genotypes was higher in females compared with males. Hypothalamic
corticotropin-like intermediate peptide content was higher in wild-type females
compared with wild-type, but not N221D, males. Taken together, these data
suggest that the increased obesity risk linked to the N221D allele in humans may
be due in part to PC1/3-induced loss of resilience to stressors rather than
strictly to decreased enzymatic activity on peptide precursors.




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