Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1999-02-02
2001-10-09
Mertz, Prema (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S387100, C530S387300, C530S388100, C530S388150, C530S388230, C530S389100, C530S389200, C424S139100, C424S141100, C424S142100, C424S145100
Reexamination Certificate
active
06300477
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. More particularly, the polypeptide of the present invention has been putatively identified as human cystatin E, sometimes hereinafter referred to as “CysE”. The invention also relates to inhibiting the action of such polypeptides.
BACKGROUND OF THE INVENTION
The cystatin superfamily comprises a group of cysteine proteinase inhibitors which are widely distributed in human tissues and body fluids, and which form tight and reversible complexes with cysteine proteinases such as cathepsins B, H, L, and S. The cystatins are most likely involved in the regulation of normal or pathological processes in which these proteinases participate. Thus, cystatins may influence the intra- and extracellular catabolism of proteins and peptides (Barret, A. J. and Kirchke, H., Methods Enzymol., 80:535-561 (1981)), regulate proteolytic processing of pro-hormones (Orlowski, M., Mol. Cell. Biochem., 52:49-74 (1983)) and pro-enzymes (Taugner, R., et al., Histochemistry, 83:103-108 (1985)), protect against penetration of normal tissues by malignant cells (Sloane, B. F., Semin. Cancer Biol., 1:137-152 (1990)) or microorganisms (Bjorck, L., et al., Nature, 337:385-386 (1989) and Bjorck, L., et al., J. Virol., 64:941-943 (1990)) and modulate local inflammatory processes in rheumatoid arthritis (Mort, J. S., et al., Arthritis Rheum., 27:509-515 (1984)) and purulent bronchiectasis (Buttle, D. J., et al., Scand. J. Clin. Lab. Invest., 50:509-516 (1990)).
The cystatin superfamily has been sub-divided into families I, II and III (also called the stefin, cystatin and kininogen families, respectively), each with members differing from those of the other families in structural organization and biological distribution (Barret, A. J., et al., Biochem. J., 236:312 (1986)). The family I cystatins A and B are small proteins consisting of single polypeptide chains of about 100 amino acid residues without disulfide bridges. The family II cystatins consist of polypeptide chains of approximately 120 amino acid residues with two intra-chain disulfide bonds. Finally, the family III cystatins, the kininogens, display a higher degree of structural complexity characterized by the presence of three family II cystatin-like domains, each with two disulfide bridges at positions homologous to those in family II cystatins (Muller-Esterl, W., et al., Transbiochem. Sci., 11:336-339 (1986)). Family I and II cystatins are mainly present intracellularly and in secretory fluids (Abrahamson, M., et al., J. Biol. Chem., 261:11282-11289 (1986)), whereas kininogens are highly concentrated in blood plasma (Adam, A., et al., Clin. Chem., 31:423-426 (1985)).
At least one type II cystatin, designated cystatin C, appears to be expressed in all tissues (Abrahamson, M., et al.,
Biochem. J.,
268:287-294 (1990)). In contrast, S-type cystatins are found predominantly in saliva (Abrahamson, M., et al.,
J. Biol. Chem.,
261:11282-11289 (1986)). Cystatins and derivative peptides possess antibacterial and antiviral activities (Bjorck, et al. (1989, 1990)), consistent with their presence in secretions bathing epithelial surfaces directly exposed to the environment. The cystatins may also modulate the immune response. This could occur directly, by inhibiting cysteine protease releases by macrophages (Bieth, J.,
Cysteine Proteinases and Their Inhibitors,
V. Turk, ed. (Walter De Gruyter & Company, New York) pp. 693-703 (1986)), or indirectly, by inhibiting the chemotaxic response and the phagocytosis-associated respiratory burst of the cells (Leung-Tack, et al.,
Biol. Chem.,
371:255-258 (1990)). This data suggests that type II cystatins might perform a variety of protective functions at epithelial surfaces. The human type II cystatin gene family consists of at least seven members.
The disease hereditary cystatin C amyloid angiopathy (HCCAA) is associated with a Glu to Leu mutation in the gene encoding cystatin C. This leads to deposition of amyloid fibrils comprised of this mutant cystatin C in the cerebral arteries, which appears to cause fatal hemorrhaging (Ghiso, J., et al.,
PNAS, USA,
83:2974-2978 (1986)).
The polypeptide of the present invention has been putatively identified as a CysE as a result of amino acid sequence homology to cystatin C and on conservation of cystatin-like functional motifs in its amino acid sequence.
SUMMARY OF THE INVENTION
The present invention provides isolated nucleic acid molecules comprising a polynucleotide encoding the CysE polypeptide having the amino acid sequence shown in
FIG. 1
(SEQ ID NO:2) or the amino acid sequence encoded by the cDNA clone deposited in a bacterial host as American Type Culture Collection (ATCC® located at 10801 University Boulevard, Manassas Va. 20120-2209, USA) Deposit Number 97156 on May 22, 1995. The nucleotide sequence determined by sequencing the deposited CysE clone, which is shown in
FIG. 1
(SEQ ID NO:1), contains an open reading frame encoding a polypeptide of 149 amino acid residues, with a leader sequence of about 28 amino acid residues, and a predicted molecular weight of about 14 kDa. The amino acid sequence of the mature CysE protein is shown in
FIG. 1
, amino acid residues 29-149 (SEQ ID NO:2).
Thus, one aspect of the invention provides an isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence selected from the group consisting of: (a) a nucleotide sequence encoding the CysE polypeptide having the complete amino acid sequence in
FIG. 1
(SEQ ID NO:2); (b) a nucleotide sequence encoding the mature CysE polypeptide having the amino acid sequence at positions 29-149 in
FIG. 1
(SEQ ID NO:2); (c) a nucleotide sequence encoding the CysE polypeptide having the complete amino acid sequence encoded by the cDNA clone contained in ATCC® Deposit No. 97156; (d) a nucleotide sequence encoding the mature CysE polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC® Deposit No. 97156; and (e) a nucleotide sequence complementary to any of the nucleotide sequences in (a), (b), (c) or (d) above.
Further embodiments of the invention include isolated nucleic acid molecules that comprise a polynucleotide having a nucleotide sequence at least 90% identical, and more preferably at least 95%, 96%, 97%, 98% or 99% identical, to any of the nucleotide sequences in (a), (b), (c), (d) or (e), above, or a polynucleotide which hybridizes under stringent hybridization conditions to a polynucleotide in (a), (b), (c), (d) or (e), above. This polynucleotide which hybridizes does not hybridize under stringent hybridization conditions to a polynucleotide having a nucleotide sequence consisting of only A residues or of only T residues. An additional nucleic acid embodiment of the invention relates to an isolated nucleic acid molecule comprising a polynucleotide which encodes the amino acid sequence of an epitope-bearing portion of a CysE polypeptide having an amino acid sequence in (a), (b), (c) or (d), above.
The present invention also relates to recombinant vectors, which include the isolated nucleic acid molecules of the present invention, and to host cells containing the recombinant vectors, as well as to methods of making such vectors and host cells and for using them for production of CysE polypeptides or peptides by recombinant techniques.
The invention further provides an isolated CysE polypeptide having an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of the CysE polypeptide having the complete 149 amino acid sequence, including the leader sequence shown in
FIG. 1
(SEQ ID NO:2); (b) the amino acid sequence of the mature CysE polypeptide (without the leader) having the amino acid sequence at positions 29-149 in
FIG. 1
(SEQ ID NO:2); (c) the amino acid sequence of the CysE polypeptide having the complete amino acid sequence, including the leader, enco
Gentz Reiner L.
Ni Jian
Rosen Craig A.
Yu Guo-Liang
Human Genome Sciences Inc.
Human Genome Sciences Inc.
Mertz Prema
LandOfFree
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