AARS Protein Fragment Segmentation for Novel Signaling Discovery
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Solution Overview
Problem
Aminoacyl-tRNA synthetases (AARSs) have been primarily studied for their role in protein translation, but their protein fragments, known as resectins, possess unexpected extracellular signaling activities and other non-canonical biological activities that have not been systematically explored for diagnostic and therapeutic applications.
Innovation Solution
Identification and characterization of AARS protein fragments, including Leucyl tRNA synthetase resectins, through mass spectrometry, deep sequencing, and bioinformatics, to develop them as biotherapeutic agents, diagnostic tools, and drug targets for various diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AARS full-length sequences are studied for their canonical aminoacylation function, then the understanding of protein translation is improved, but the discovery of novel extracellular signaling activities is hindered
Solution Approach 1:
The patent applies segmentation by systematically analyzing and isolating specific protein fragments (resectins) from full-length AARS sequences. Mass spectrometry and deep sequencing were used to identify distinct N-terminal, C-terminal, and internal fragments, allowing each segment to be characterized for its unique biological activities separate from the canonical aminoacylation function of the full-length protein
Solution Approach 2:
The patent extracts and removes the resectin fragments from their parental full-length AARS sequences to study their independent functions. This extraction process revealed that the fragments possess novel extracellular signaling activities that are masked when embedded in the full-length protein context, enabling independent characterization of these non-canonical functions
2Reliability
If standard genomic sequencing and bioinformatics are used to identify AARS functions, then the canonical aminoacylation role is confirmed, but resectins with non-synthetase activities are missed
Solution Approach 1:
The patent overcomes the limitation of standard genomic sequencing by applying segmentation through mass spectrometry-based proteomics and deep sequencing of transcriptomes. These techniques systematically parse full-length AARS sequences into identifiable fragment regions, revealing resectins that conventional bioinformatics approaches had overlooked
Solution Approach 2:
The patent transitions from the traditional single-dimension genomic sequencing approach to multiple dimensions by combining mass spectrometry proteomics, deep sequencing, and targeted bioinformatics analysis. This multi-dimensional approach enables detection of resectins that exist as separate functional entities with non-synthetase activities
3Loss of energy
If AARS fragments are not systematically analyzed, then research resources are conserved, but the therapeutic and diagnostic potential of resectins remains unexplored
Solution Approach 1:
The patent applies preliminary action by conducting comprehensive systematic analysis of all AARS fragments before pursuing therapeutic development. Mass spectrometry, deep sequencing, and functional assays were performed upfront to characterize resectin properties, ensuring that subsequent therapeutic and diagnostic applications are based on well-understood fragment functionalities
Solution Approach 2:
The patent demonstrates that AARS fragments serve multiple functions beyond the canonical aminoacylation role. The systematic analysis revealed that different resectins possess diverse biological activities including extracellular signaling, making them versatile candidates for multiple therapeutic and diagnostic applications across different disease states
Data Source
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AI summary
Provided are compositions comprising newly identified protein fragments of aminoacyl-tRNA synthetases, polynucleotides that encode them and complements thereof, related agents, and methods of use thereof in diagnostic, drug discovery, research, and therapeutic applications.