Plasminogen (Pg) activators such as streptokinase (SK) save lives by generating plasmin to dissolve blood clots. Some believe that the unique ability of SK to activate Pg in the absence of fibrin limits its therapeutic utility. We have found that SK contains an unusual NH(2)-terminal "catalytic switch" that allows Pg activation through both fibrin-independent and fibrin-dependent mechanisms. Unlike SK, a mutant (rSKDelta59) fusion protein lacking the 59 NH(2)-terminal residues was no longer capable of fibrin-independent Pg activation (k(cat)/K(m) decreased by >600-fold). This activity was restored by coincubation with equimolar amounts of the NH(2)-terminal peptide rSK1-59. Deletion of the NH(2) terminus made rSKDelta59 a Pg activator that requires fibrin, but not fibrinogen, for efficient catalytic function. The fibrin-dependence of the rSKDelta59 activator complex apparently resulted from selective catalytic processing of fibrin-bound Pg substrates in preference to other Pg forms. Consistent with these observations, the presence (rSK) or absence (rSKDelta59) of the SK NH(2)-terminal peptide markedly altered fibrinolysis of human clots suspended in plasma. Like native SK, rSK produced incomplete clot lysis and complete destruction of plasma fibrinogen; in contrast, rSKDelta59 produced total clot lysis and minimal fibrinogen degradation. These studies indicate that structural elements in the NH(2) terminus are responsible for SK's unique mechanism of fibrin-independent Pg activation. Because deletion of the NH(2) terminus alters SK's mechanism of action and targets Pg activation to fibrin, there is the potential to improve SK's therapeutic efficacy.
Pharmacology, Toxicology and Pharmaceutical Science
2
11%
Earth and Planetary Sciences
1
5%
Medicine and Dentistry
1
5%
Other
0
0%
Unknown
7
37%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 9. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 February 2017.
All research outputs
#5,145,798
of 34,400,738 outputs
Outputs from Proceedings of the National Academy of Sciences of the United States of America
#48,619
of 118,992 outputs
Outputs of similar age
#6,183
of 51,328 outputs
Outputs of similar age from Proceedings of the National Academy of Sciences of the United States of America
#126
of 507 outputs
Altmetric has tracked 34,400,738 research outputs across all sources so far. Compared to these this one has done well and is in the 83rd percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 118,992 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 40.1. This one has gotten more attention than average, scoring higher than 52% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 51,328 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 79% of its contemporaries.
We're also able to compare this research output to 507 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 58% of its contemporaries.
