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Creation of lysine-deficient mutant lymphotoxin-α with receptor selectivity by using a phage display system

Paper ID Volume ID Publish Year Pages File Format Full-Text
9383 627 2010 9 PDF Available
Title
Creation of lysine-deficient mutant lymphotoxin-α with receptor selectivity by using a phage display system
Abstract

The cytokine lymphotoxin-α (LTα) activates various biological functions through its three receptor subtypes, tumor necrosis factor receptor 1 (TNFR1), TNFR2 and herpes virus entry mediator (HVEM), but the relative contribution of each receptor to each function is unclear. Therefore it is important to create mutant LTα with receptor selectivity for optimized cancer therapy and the analysis of receptor function. Here, we attempted to create a lysine-deficient mutant LTα with TNFR1-selective bioactivity using a phage display technique. We obtained the TNFR1-selective mutant LTα R1selLT, which contained the mutations K19N, K28Q, K39S, K84Q, K89V, and K119H. Compared with wild-type LTα (wtLTα), R1selLT showed several-fold higher bioactivity via TNFR1 but 40-fold lower bioactivity via TNFR2. Kinetic association–dissociation parameters of R1selLT with TNFR2 were higher than those of wtLTα, whereas these parameters of R1selLT with TNFR1 were lower than those of wtLTα, suggesting that destabilization of the R1selLT–TNFR2 complex causes the decreased bioactivity of R1selLT on TNFR2. We also showed that the K84Q mutation contributed to the enhanced activity via TNFR1, and K39S lowered activity via TNFR2. R1selLT likely will be useful in cancer therapy and in analysis of the LTα structure–function relationship.

Keywords
Affinity; Bioactivity; Cytokine; Molecular modeling; Recombinant protein
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Creation of lysine-deficient mutant lymphotoxin-α with receptor selectivity by using a phage display system
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Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 31, Issue 7, March 2010, Pages 1935–1943
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us