Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of Histidyl-tRNA synthetases
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.
1. A therapeutic composition, comprising an isolated aminoacyl-tRNA synthetase (AARS) polypeptide that is at least 95%, 98%, or 100% identical to a sequence selected from:
(a) SEQ ID NO: 109, or a fragment thereof which is 120 or more contiguous amino acids of SEQ ID NO:109;
(b) SEQ ID NO: 64 or 83, or a fragment thereof which is 90 or more contiguous amino acids of SEQ ID NO: 64 or 83; and
(c) SEQ ID NO: 48, 52, 54, or 58, or a fragment thereof which is 360 or more contiguous amino acids of SEQ ID NO: 48, 52, 54, or 58,
wherein the AARS polypeptide has an extracellular signaling activity and a solubility of at least about 5 mg/mL, and wherein the composition has a purity of at least about 95% on a protein basis and less than about 10 EU endotoxin/mg protein.
2. The therapeutic composition of claim 1 , wherein the AARS polypeptide consists of an amino acid sequence selected from SEQ ID NOs: 109, 64, 83, 48, 52, 54, and 58 or differs from an amino acid sequence selected from SEQ ID NOs: 109, 64, 83, 48, 52, 54, and 58 by substitution, deletion, and/or addition of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acids.
3. The therapeutic composition of claim 1 , wherein the AARS polypeptide is fused to a heterologous polypeptide.
4. The therapeutic composition of claim 1 , wherein at least one moiety or a solid substrate is covalently or non-covalently attached to said polypeptide.
5. An isolated aminoacyl-tRNA synthetase (AARS) polypeptide that is at least 95%, 98%, or 100% identical to an amino acid sequence selected from
(a) SEQ ID NO: 109, or a fragment thereof which is 120 or more contiguous amino acids of SEQ ID NO:109;
(b) SEQ ID NO: 64 or 83, or a fragment thereof which is 90 or more contiguous amino acids of SEQ ID NO: 64 or 83; and
(c) SEQ ID NO: 48, 52, 54, or 58, or a fragment thereof which is 360 or more contiguous amino acids of SEQ ID NO: 48, 52, 54, or 58,
wherein the AARS polypeptide has an extracellular signaling activity.
6. The isolated AARS polypeptide of claim 5 , wherein the AARS polypeptide is fused to a heterologous polypeptide.
7. The isolated AARS polypeptide of claim 5 , further comprising an element selected from the group consisting of:
(i) an engineered population of cells in which at least one cell comprises a polynucleotide encoding said AARS polypeptide, wherein the cells are capable of growing in a serum-free medium;
and
(ii) an engineered population of cells in which at least one cell comprises a polynucleotide encoding said AARS polypeptide, at least about 10 liters of a serum-free growth medium, and a sterile container.
8. A method of determining presence or levels of an AARS polypeptide or a polynucleotide that encodes the AARS polypeptide in a sample, comprising:
(a) contacting the sample with one or more binding agents or antibodies or antigen-binding fragments thereof that specifically bind to an AARS polypeptide of claim 5 , detecting the presence or absence of the binding agent, and thereby determining the presence or levels of the AARS polypeptide;
(b) analyzing the sample with a detector that is capable of specifically identifying an AARS polypeptide of claim 5 , and thereby determining the presence or levels of the AARS polypeptide;
(c) contacting the sample with one or more oligonucleotides that specifically hybridize to polynucleotide that encodes an AARS polypeptide of claim 5 , detecting the presence or absence of the oligonucleotides in the sample, and thereby determining the presence or levels of the polynucleotide; or
(d) contacting the sample with at least two oligonucleotides that specifically amplify a polynucleotide that encodes an AARS polypeptide of claim 5 , performing an amplification reaction, detecting the presence or absence of an amplified product, and thereby determining presence or levels of the polynucleotide.
9. A method of modulating a cellular activity of a cell, or protein, comprising contacting the cell or protein with an AARS polypeptide claim 5 , or a composition comprising a pharmaceutically-acceptable carrier and said AARS polypeptide.
10. The method of claim 9 , wherein the cell or protein is in a subject having a disease or disorder optionally mediated by the dysregulation of the expression, activity or spatiotemporal location of a tRNA synthetase, comprising administering the AARS polypeptide or the composition to the subject.
11. A composition, comprising (a) an antibody or antigen binding fragment thereof that exhibits binding specificity for an AARS polypeptide of claim 5 , or (b) an isolated polynucleotide that encodes an AARS polypeptide of claim 5 .
12. A method of identifying a compound that specifically binds to an AARS polypeptide of claim 5 , comprising a) combining the AARS polypeptide with at least one test compound under suitable conditions, and b) detecting binding of the AARS polypeptide to the test compound, thereby identifying a compound that specifically binds to the AARS polypeptide.