Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1997-11-25
2001-02-13
Draper, Garnette D. (Department: 1647)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C530S351000, C530S399000, C530S395000, C514S002600, C514S008100, C514S012200, C514S909000
Reexamination Certificate
active
06187908
ABSTRACT:
This application claims the benefit of priority of UK patent application number 9624433.0 filed on Nov. 25, 1996, and of European patent application number 97307877.7 filed on Oct. 6, 1997.
FIELD OF INVENTION
This invention relates to newly identified polynucleotides, polypeptides encoded by them and to the use of such polynucleotides and polypeptides, and to their production. More particularly, the polynucleotides and polypeptides of the present invention relate to the Tubby related polypeptides family, hereinafter referred to as Tubby 2. The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides.
BACKGROUND OF THE INVENTION
The mouse tubby gene has been shown to be mutated in the so-called ‘Tubby’ mouse model (Kleyn, PW et al (1996) Cell 85, 281-290; Noben-Trauth, K et al. (1996) Nature 380: 534-538). Mutant mice exhibit weight gain from age 6 months and develop insulin resistance associated with this weight gain. There is also evidence of increased susceptibility to atherosclerosis and dyslipidemia in these mutant mice. Kleyn et al. also describe the human orthologue of the mouse tubby gene. It is suggested that changes in the tubby polypeptide are relevant to human weight gain disorders. Kleyn et al however provide no description of the biochemical or signalling properties of the tubby protein.
International patent application, publication number WO 96/05861, relates to compositions and methods for the treatment of bodyweight disorders and in particular identifies certain genes which are used in these composition and methods.
There is a need for identification and characterization of further members of the Tubby related polypeptides family which can play a role in preventing, ameliorating or correcting dysfunctions or diseases.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to Tubby 2 polypeptides and recombinant materials and methods for their production. Another aspect of the invention relates to methods for using such Tubby 2 polypeptides and polynucleotides. Such uses include the treatment of diabetes, obesity, and atherosclerosis, among others. In still another aspect, the invention relates to methods to identify agonists and antagonists using the materials provided by the invention, and treating conditions associated with Tubby 2 imbalance with the identified compounds. Yet another aspect of the invention relates to diagnostic assays for detecting diseases associated with inappropriate Tubby 2 activity or levels.
DESCRIPTION OF THE INVENTION
Polypeptides of the Invention
In a first aspect, the present invention relates to Tubby 2 polypeptides and variants and fragments thereof. Such polypeptides include isolated polypetides comprising an amino acid sequence which has at least 70% identity, preferably at least 80% identity, more preferably at least 90% identity, yet more preferably at least 95% identity, most preferably at least 97-99% identity, to that of SEQ ID NO:2 over the entire length of SEQ ID NO:2. Such polypeptides include those comprising the amino acid of SEQ ID NO:2.
Tubby 2 polypeptides also include isolated polypeptides in which the amino acid sequence has at least 70% identity, preferably at least 80% identity, more preferably at least 90% identity, yet more preferably at least 95% identity, most preferably at least 97-99% identity, to the amino acid sequence of SEQ ID NO:2 over the entire length of SEQ ID NO:2. Such polypeptides include the polypeptide of SEQ ID NO:2.
The Tubby 2 polypeptides may be in the form of the “mature” protein or may be a part of a larger protein such as a fusion protein. It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification such as multiple histidine residues, or an additional sequence for stability during recombinant production.
Fragments of the Tubby 2 polypeptides are also included in the invention. A fragment is a polypeptide having an amino acid sequence that entirely is the same as part, but not all, of the amino acid sequence of the aforementioned Tubby 2 polypeptides. As with Tubby 2 polypeptides, fragments may be “free-standing,” or comprised within a larger polypeptide of which they form a part or region, most preferably as a single continuous region. Representative examples of polypeptide fragments of the invention, include, for example, fragments from about amino acid number 1-20, 21-40, 41-60, 61-80, 81-100, and 101 to the end of Tubby 2 polypeptide. In this context “about” includes the particularly recited ranges larger or smaller by several, 5, 4, 3, 2 or 1 amino acid at either extreme or at both extremes.
Preferred fragments include, for example, truncation polypeptides having the amino acid sequence of Tubby 2 polypeptides, except for deletion of a continuous series of residues that includes the amino terminus, or a continuous series of residues that includes the carboxyl terminus or deletion of two continuous series of residues, one including the amino terminus and one including the carboxyl terminus. Also preferred are fragments characterized by structural or functional attributes such as fragments that comprise alpha-helix and alpha-helix forming regions, beta-sheet and beta-sheet-forming regions, turn and turn-forming regions, coil and coil-forming regions, hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, flexible regions, surface-forming regions, substrate binding region, and high antigenic index regions. Other preferred fragments are biologically active fragments. Biologically active fragments are those that mediate Tubby 2 activity, including those with a similar activity or an improved activity, or with a decreased undesirable activity. Also included are those that are antigenic or immunogenic in an animal, especially in a human.
Variants of the defined sequence and fragments also form part of the present invention. Preferred variants are those that vary from the referents by conservative amino acid substitutions—i.e., those that substitute a residue with another of like characteristics. Typical such substitutions are among Ala, Val, Leu and Ile; among Ser and Thr; among the acidic residues Asp and Glu; among Asn and Gln; and among the basic residues Lys and Arg; or aromatic residues Phe and Tyr. Particularly preferred are variants in which several, 5-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination.
The Tubby 2 polypeptides of the invention can be prepared in any suitable manner. Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art.
Polynucleotides of the Invention
In a further aspect, the present invention relates to Tubby 2 polynucleotides. Such polynucleotides include isolated polynucleotides comprising a nucleotide sequence which has at least 70% identity, preferably at least 80% identity, more preferably at least 90% identity, yet more preferably at least 95% identity, to a nucleotide sequence encoding the polypeptide of SEQ ID NO:2, over the entire coding region. In this regard, polynucleotides which have at least 97% identity are highly preferred, whilst those with at least 98-99% identity are more highly preferred, and those with at least 99% identity are most highly preferred. Such polynucleotides include a polynucleotide comprising the nucleotide sequence contained in SEQ ID NO:1 encoding the polypeptide of SEQ ID NO:2.
Tubby 2 polynucleotides further includes isolated polynucleotides comprising a nucleotide sequence which has at least 70% identity, preferably at least 80% identity, more preferably at least 90% identity, yet more preferably at least 95% identity, to SEQ ID NO:1 over the entire length of SEQ ID NO:1. In this regard, polynucleotides which have at least 97% identity are highly preferred, whilst those with at lea
Doe Trudy Rachel
Gloger Israel Simon
Hughes Stephen A.
Terrett Jonathan Alexander
Testa Tania Tamson
Draper Garnette D.
Han William T.
King William T.
Ratner & Prestia
SmithKline Beecham p.l.c.
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