SMNΔ7 Degron Mutation for Spinal Muscular Atrophy
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Solution Overview
Problem
Spinal muscular atrophy (SMA) patients suffer from SMN protein deficiency due to the instability of the SMNΔ7 protein, which is caused by a specific protein destabilization signal, leading to impaired mRNA metabolism and severe clinical phenotypes.
Innovation Solution
Identification and utilization of a novel protein destabilization signal, referred to as the SMNΔ7-degron, which is sufficient to induce protein instability, along with a point mutation SMNΔ7 S270A that enhances protein stability, to prevent SMN degradation and increase the viability of SMN-depleted cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If SMNΔ7 protein is expressed to compensate for SMN deficiency, then the quantity of SMN protein increases, but the protein is rapidly degraded due to the degron sequence, reducing its stability and functional effectiveness
Solution Approach 1:
The invention extracts and removes the harmful degron sequence (YG+EMLA) from the SMNΔ7 protein through targeted mutagenesis. By eliminating this specific destabilizing element, the protein stability is restored while preserving the beneficial splicing pattern that increases SMN quantity.
Solution Approach 2:
The invention changes the amino acid sequence parameters of SMNΔ7 by introducing point mutations (S270A, G272A) that alter the protein's stability characteristics. These parameter changes in the protein sequence prevent degron recognition and extend protein half-life.
2Quantity of substance
If the SMNΔ7 protein is produced through SMN2 splicing to increase SMN levels, then the quantity of SMN protein increases, but the protein acquires a destabilizing sequence that reduces its functional effectiveness
Solution Approach 1:
The invention converts the harmful effect of the degron sequence into a beneficial therapeutic strategy. By specifically targeting and mutating the degron sequence while preserving the overall SMNΔ7 structure and splicing pattern, the therapy maintains the increased protein quantity advantage while eliminating the functionality-reducing degradation.
Solution Approach 2:
The invention applies local quality modification by making specific point mutations only at the degron region (amino acids 268-274) while leaving the rest of the SMNΔ7 protein sequence unchanged. This localized change preserves the beneficial aspects of SMNΔ7 while correcting the specific functional defect.
3Stability of the object's composition
If proteasome inhibition is used to prevent SMNΔ7 degradation, then the protein stability increases, but the approach lacks specificity and may have off-target effects
Solution Approach 1:
The invention extracts the specific cause of degradation (the degron sequence) and removes it through targeted mutagenesis, eliminating the need for broad proteasome inhibition. This specific approach targets only the problematic SMNΔ7 protein rather than affecting all proteasome-dependent degradation pathways.
Solution Approach 2:
Instead of preventing degradation by inhibiting the proteasome system broadly, the invention inverts the approach by modifying the SMNΔ7 protein itself to prevent recognition by the degradation machinery. This shifts the solution from blocking the degradation system to making the target protein degradation-resistant.
Data Source
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AI summary
The present invention includes an isolated nucleic acid comprising a nucleic acid sequence encoding a SMN?7 degron and the encoded polypeptide. The invention also includes inhibitors of SMN?7 degron. The invention also includes compositions and methods for mitigating SMN deficiency by targeting inhibition of factors that mediate SMN?7-degron dependent degradation of SMN?7.