Chimeric proteins and methods of regulating gene expression
First Claim
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1. A system for regulating expression of a target polynucleotide in a cell, the system comprising:
- (a) a chimeric receptor polypeptide comprising a transmembrane receptor or a fragment thereof, that undergoes a receptor modification including a conformational change or chemical modification upon binding to its ligand, wherein the chimeric receptor polypeptide comprises a cleavage moiety that cleaves a cleavage recognition site; and
(b) a chimeric adaptor polypeptide that binds the chimeric receptor polypeptide in response to the receptor modification, wherein the chimeric adaptor polypeptide comprises a gene modulating polypeptide (GMP) comprising an actuator moiety linked to the cleavage recognition site;
wherein the cleavage moiety cleaves the cleavage recognition site when in proximity to the cleavage recognition site and in response to receptor binding to the ligand, and wherein upon cleaving the cleavage recognition site, the actuator moiety regulates expression of the target polynucleotide.
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Abstract
The present disclosure provides systems, compositions and methods for regulating expression of a target polynucleotide in a cell. The systems, compositions and methods comprise a chimeric receptor polypeptide comprising a G-protein coupled receptor (GPCR) or a fragment thereof, a chimeric adaptor polypeptide, at least one actuator moiety and a cleavage moiety.
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Citations
30 Claims
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1. A system for regulating expression of a target polynucleotide in a cell, the system comprising:
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(a) a chimeric receptor polypeptide comprising a transmembrane receptor or a fragment thereof, that undergoes a receptor modification including a conformational change or chemical modification upon binding to its ligand, wherein the chimeric receptor polypeptide comprises a cleavage moiety that cleaves a cleavage recognition site; and (b) a chimeric adaptor polypeptide that binds the chimeric receptor polypeptide in response to the receptor modification, wherein the chimeric adaptor polypeptide comprises a gene modulating polypeptide (GMP) comprising an actuator moiety linked to the cleavage recognition site; wherein the cleavage moiety cleaves the cleavage recognition site when in proximity to the cleavage recognition site and in response to receptor binding to the ligand, and wherein upon cleaving the cleavage recognition site, the actuator moiety regulates expression of the target polynucleotide. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
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16. A method of regulating expression of a target polynucleotide in a cell, the method comprising:
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(a) contacting a ligand to a chimeric transmembrane receptor polypeptide comprising a cleavage moiety, wherein the chimeric transmembrane receptor polypeptide is modified upon contacting to the ligand, and wherein the receptor modification comprises a conformational change or a chemical modification; (b) binding a chimeric adaptor polypeptide comprising a gene modulating polypeptide (GMP) to the chimeric transmembrane receptor polypeptide in response to the receptor modification, wherein the GMP comprises an actuator moiety linked to a cleavage recognition site; and (c) cleaving the cleavage recognition site with the cleavage moiety to release the actuator moiety, wherein upon said release, the actuator moiety regulates expression of the target polynucleotide in the cell. - View Dependent Claims (17, 18, 19, 20, 21, 22, 23, 24, 25)
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26. A chimeric adaptor polypeptide comprising:
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(a) a receptor binding moiety that binds a receptor that has undergone a modification upon binding to a ligand; and (b) a gene modulating polypeptide (GMP) linked to the receptor binding moiety, wherein the GMP comprises an actuator moiety linked to a cleavage recognition site; wherein;
(i) the cleavage recognition site is cleavable by a cleavage moiety in response to the receptor modification; and
(ii) the actuator moiety is operable to complex with a target polynucleotide in response to cleavage of the cleavage recognition site. - View Dependent Claims (27, 28, 29, 30)
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Specification