Mutant Unc93b1 Proteins Modulate TLR5 Trafficking and Signaling
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Solution Overview
Problem
Current methods fail to effectively modulate the trafficking and signaling of Toll-Like Receptor 5 (TLR5), which is crucial for immune responses, leading to imbalances in immune activation and potential diseases such as inflammatory bowel disease and increased susceptibility to infections.
Innovation Solution
Development of mutant Unc93b1 proteins with specific amino acid mutations that modulate the trafficking and signaling of TLR5, either increasing or decreasing its activity to treat diseases related to abnormal TLR5 expression or activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current methods are used to modulate TLR5, then immune response regulation is attempted, but the modulation is ineffective and does not achieve desired therapeutic outcomes
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations in the Unc93b1 protein (e.g., D34A, Y99A, Y154A, K197A, H412R, and various deletions and substitutions) to alter the protein's function. These mutations change the biochemical parameters of Unc93b1, enabling effective modulation of TLR5 trafficking and signaling that previous methods failed to achieve, thereby resolving the contradiction between reliability of modulation and regulatory efficiency
Solution Approach 2:
The patent uses mutant Unc93b1 proteins as intermediary molecules to mediate the modulation of TLR5. The Unc93b1 protein serves as a mediator that controls TLR5 trafficking between endosomes and the plasma membrane. By engineering specific mutations in this intermediary protein, the patent achieves effective TLR5 modulation without directly targeting TLR5 itself, resolving the ineffectiveness of current direct modulation methods
2Reliability
If TLR5 activity is increased to enhance immune response, then protection against infections improves, but risk of inflammatory diseases increases
Solution Approach 1:
The patent applies dynamics by creating a tunable system where TLR5 activity can be dynamically adjusted rather than fixed. Different mutant Unc93b1 proteins provide different levels of TLR5 modulation, allowing the immune response to be dynamically regulated based on specific therapeutic needs. This enables clinicians to select appropriate mutation profiles to achieve desired immune activation levels without excessive inflammation, resolving the contradiction between infection protection and inflammatory disease risk
Solution Approach 2:
The patent applies local quality by introducing specific point mutations at particular amino acid positions in the Unc93b1 protein structure. Each mutation location (e.g., D34A, Y99A, Y154A, K197A, H412R) creates localized changes in protein function that selectively modulate TLR5 trafficking. This localized modification approach allows precise control over immune activation levels, enabling enhanced infection protection while minimizing systemic inflammatory risks through targeted functional changes
3Object-affected harmful factors
If TLR5 activity is decreased to reduce inflammation, then inflammatory disease symptoms improve, but susceptibility to infections increases
Solution Approach 1:
The patent applies dynamics by providing a spectrum of mutant Unc93b1 proteins that offer graded levels of TLR5 suppression. Rather than complete inhibition, the dynamic range of mutant proteins allows selective reduction of TLR5 activity to sufficient levels for inflammatory disease management while maintaining adequate immune surveillance. This dynamic modulation resolves the contradiction by enabling adjustable suppression that prevents both excessive inflammation and complete immune compromise
Solution Approach 2:
The patent applies local quality through specific amino acid mutations that locally alter Unc93b1 function to selectively dampen TLR5 signaling. Mutations such as D34A, Y99A, Y154A, and others create localized functional changes that preferentially affect TLR5 trafficking and signaling pathways involved in inflammatory responses. This localized functional modification allows selective reduction of inflammatory pathology while preserving essential anti-infective immune functions through controlled local changes in protein behavior
Data Source
AI summary
Disclosed herein are Unc93b1 mutations that modulated the trafficking and/or signaling of TLR5, and compositions and methods of using thereof.