Peptide sequence that forms mucin sugar chain and technique for

Details Peptide sequence that forms mucin sugar chain and technique for Peptide sequence that forms mucin sugar chain and technique for

1996-09-19

1998-12-01

Prouty, Rebecca E.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

435 701, 4351721, 4353201, 435325, 536 231, 536 234, 935 22, C12P 2106, C12P 2104, C12N 500, C07H 2102

Patent

active

058437134

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention relates to amino acid sequences with which a mucin type sugar chain can be introduced into a protein or peptide and also relates to a technique for introducing a mucin type sugar chain into a protein or peptide by utilizing the sequences.
2. Background Art
Many of the proteins found in animals, plants and insects are glycoproteins. A wide variety of roles of the sugar chains of glycoprotein has been unveiled in recent years. For example, it is known that a sugar chain has physiological roles as a ligand in cell adhesion and cell recognition as well as a physicochemical role of improving the stability and/or solubility of proteins. In addition, while glycoproteins such as erythropoietin and interferons have been developed as a drug recent years, the structure of the sugar chain on the glycoproteins has a great influence on the pharmacokinetics and the stability of the drugs in vivo. Although the significance of the sugar chains of glycoprotein has been well recognized, no established techniques have been known so far for introducing a sugar chain into a specific position of a protein in a simple manner.
For some drugs that are inherently glycoprotein, their protein portions are only prepared typically with E. coli on a mass production basis. When such a protein is administered as a drug, the kinetics, stability and antigenicity of the protein in vivo sometimes differ from the native glycoprotein due to lack of sugar chains. The differences may, by turn, give rise to problems including impairment with a large dose and side effect.
Even proteins produced in animal cells can become glycoproteins having sugar chains that are different from the native ones. Then, such proteins can also entail the problems as mentioned above.
The above problems and other related problems may be dissolved by a technique of introducing a specific sugar chain into a specific position of a protein molecule. Further, various functional features of sugar chains can be selectively introduced into the protein with such a technique. Furthermore, the technique will show a wide variety of applications in the pharmaceutical industry and other industries.
Two major modes of binding a sugar chain to protein have been known; an asparagine linked type sugar chain and a mucin type sugar chain.
According to previous reports, asparagine linked type sugar chains attach to a consensus sequence of -Asn-Xaa-Ser/Thr- (Xaa.noteq.Pro). However, it is also known that not all the sites having the consensus sequence in a protein have an asparagine linked type sugar chain. On the other hand, as for the mucin type sugar chain, there have been reports telling that amino acids such as Ser, Thr and Pro are frequently observed near the binding site. However, no reports have ever described the well characteristic features of the sequence of the binding site.
The asparagine linked type sugar chain differs from the mucin type sugar chain in the biosynthesis of the sugar chain. Specifically, the biosynthesis of an asparagine linked type sugar chain takes place co-translationally in protein synthesis and then the folding of glycoprotein follows it. On the other hand, a mucin type sugar chain is introduced post-translationally, i.e., after the translation and folding of protein. In addition, as for the asparagine linked type sugar chain, it has been reported that a large sugar chain having fourteen monosaccharides is at a time transferred to a protein and recognized and controlled to form a proper protein structure by a molecular chaperon called calnexin. However, no molecular chaperon is known to date for the mucin type sugar chains.
Thus, while common sequence required for glycosylation of an asparagine linked type sugar chain is well known as described above, there is no knowing where is the suitable position in a protein for introducing the sugar chain. In addition, there is no guarantee if the mutant protein having the sugar chain shows the same three dimensional structure and biological activity

REFERENCES:
Wilson et al (1991) BiocJ 275:529-534 "Amino acid distributions aroud O-linked glycosylation sites".
Brockhausen et al (1990) Biochem 29:10206-10212 "Control of Mucin synthesis: The peptide portion of . . . ".
Grabenhorst et al (1993) Eur J. Biochem 275:189-197 "Biosynthesis and secretion of human interleukin 2 glycoprotein . . . ".

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