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Polypeptide structural motifs associated with cell signaling activity

Inactive Publication Date: 2012-01-05
ATYR PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0034]In still other aspects, the polypeptides, antibodies and/or other compositions of the present invention may be used in essentially any type of screening assay known and available in the art. For example, compositions of the invention (e.g., polypeptides, polynucleotides and/or antibodies) may be used in conjunction with essentially any known screening methodology in order to identify suitable cell types and/or disease conditions amenable to treatment according to the present invention. In other examples, compositions of the invention (e.g., polypeptides, polynucleotides and/or antibodies) may be used in conjunction with known screening methodologies in order to identify binding partners, competitive inhibitors, cellular effectors, and the like, that mediate or modulate, either directly or indirectly, the cell signaling and/or non-canonical activities of the compositions herein. For example, in a partic

Problems solved by technology

Unfortunately, there are no reliable methods available for predicting or identifying which cytoplasmic proteins or polypeptide fragments derived from AARS proteins and / or other proteins may have novel and previously unappreciated activities.

Method used

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  • Polypeptide structural motifs associated with cell signaling activity
  • Polypeptide structural motifs associated with cell signaling activity
  • Polypeptide structural motifs associated with cell signaling activity

Examples

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example 1

Identification of Structural Motif within a GlyRS Polypeptide Fragment Having Cell Signaling Activity

[0297]As shown in FIGS. 2A-2C, a fragment of human glycyl-tRNA synthetase (GlyRS) referred to as G6, and corresponding to residues 214-439 of human GlyRS (SEQ ID NO: 1), was unexpectedly discovered to be effective in inducing GPCR-dependent chemotaxis of THP-1 monocytes. Further analysis of this active fragment revealed the presence of a structural motif, comprising 3 antiparallel β-sheets flanked by an α-helix at each end, believed to be responsible for the observed chemokine activity. The structural motif was identified as being contained within amino acid residues 345-438 of the human GlyRS protein sequence set forth in SEQ ID NO: 1.

example 2

Identification of Structural Motif in Other Class II AARS Proteins

[0298]The structural motif identified above in Example 1 was also found in similar regions of other human Class II AARS. These included AspRS, HisRS, ThrRS, GluProRS and SerRS. This region of Class II AARS proteins is highly conserved structurally among members of this AARS class indicating that the region contains the same basic structural architecture, but is not well conserved in residue sequence identity, creating the potential to display different sequences which may have different signaling activities on this architecture. (e.g., FIG. 4, adapted from O'Donoghue and Luthey-Schulten, Microbiology and Molecular Biology Reviews, December 2003)

[0299]The structural motif was identified as being contained within amino acid residues 367-448 of the human AspRS protein sequence set forth in SEQ ID NO: 2; within amino acid residues 294-372 of the human HisRS protein set forth in SEQ ID NO: 3; within amino acid residues 469...

example 3

Illustrative Non-AARS Proteins Containing the Structural Motif

[0300]Further analysis identified the presence of this same structural motif comprising 3 antiparallel β-sheets and two α-helices in several non-AARS proteins (FIG. 5). For example, the motif was identified in human thioredoxin, contained within residues 20-105 of the human thioredoxin sequence of SEQ ID NO: 11, as well as within residues 20-84 of Trx80, which is a truncated, secreted form of thioredoxin containing the N-terminal 84 amino acid residues.

[0301]The motif was also identified in the human macrophage inhibitory factor protein, contained within residues 1-90 of the human thioredoxin sequence of SEQ ID NO: 12.

[0302]The motif was also identified in the human peroxiredoxin 5 isoform B protein, contained within non-contiguous fragments corresponding to residues 32-68 and 125-161 of the human peroxiredoxin 5 isoform B sequence of SEQ ID NO: 13.

[0303]Thus, by screening non-AARS proteins for the presence of the identif...

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Abstract

Isolated polypeptides comprising or consisting essentially of specific structural motifs (e.g., three β-sheets and two α-helices) are provided, wherein the polypeptides exhibit at least one cell signaling and / or other non-canonical activity of biological relevance. Also provided are polynucleotides encoding such polypeptides, binding agents that bind such polypeptides, analogs, variants and fragments of such polypeptides, etc., as well as compositions and methods of identifying and using any of the foregoing.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 61 / 156,370, filed Feb. 27, 2009, which is incorporated by reference in its entirety.STATEMENT REGARDING SEQUENCE LISTING[0002]The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is 120161—411_PC_SEQUENCE_LISTING.txt. The text file is 61 KB, was created on Feb. 26, 2010, and is being submitted electronically via EFS-Web, concurrent with the filing of the specification.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The present invention relates generally to polypeptides containing structural motifs associated with cell signaling and other biologically relevant activities, compositions comprising such polypeptides, and methods of identifying and using...

Claims

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Application Information

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IPC IPC(8): A61K38/19C07H21/00C12N15/63C12N5/00G01N33/53A61P43/00G01N33/68G01N33/50C12N5/10C12N1/19C12N1/21G01N33/566C07K14/52C12Q1/68
CPCA61K38/00C07K14/521C12N9/0036C12N9/93G01N33/68G01N2333/52Y10T436/143333G01N2500/04G01N2500/10G01N2500/20C07K16/40C12Y601/01012G01N2333/9015C12Y601/01021A61P43/00C07K2317/24
Inventor GREENE, LESLIE ANN
Owner ATYR PHARM INC
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