KR101835180B1 - Recombinant BTG2 protein and production method thereof - Google Patents
Recombinant BTG2 protein and production method thereof Download PDFInfo
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- KR101835180B1 KR101835180B1 KR1020150037352A KR20150037352A KR101835180B1 KR 101835180 B1 KR101835180 B1 KR 101835180B1 KR 1020150037352 A KR1020150037352 A KR 1020150037352A KR 20150037352 A KR20150037352 A KR 20150037352A KR 101835180 B1 KR101835180 B1 KR 101835180B1
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- South Korea
- Prior art keywords
- btg2
- protein
- leu
- ser
- gly
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Abstract
본 발명은 서열번호 1로 표시되는 아미노산 서열을 코딩하는 BTG2 유전자 및 상기 유전자의 C-말단에 태깅된 헤마글루티닌(hemagglutinin; HA)을 코딩하는 유전자를 포함하는 재조합 벡터, 상기 벡터로 발현된 BTG2 단백질 및 이의 생산방법에 관한 것으로, 본 발명에 따른 벡터로 발현된 BTG2 단백질은 C-말단에 HA-태그(tag)가 결합되며, 두 개의 단백질이 합성되어 BTG2 단백질 복합체를 형성한다. 이러한 BTG2 단백질은 유비퀴틴 단백질과 결합되지 않으므로 26S 단백질분해효소 복합체(26S proteasome complex)에 분해되지 않고 세포내에서 안정적으로 발현될 수 있다.The present invention relates to a recombinant vector comprising a gene encoding BTG2 gene encoding the amino acid sequence represented by SEQ ID NO: 1 and hemagglutinin (HA) tagged at the C-terminal of the gene, The present invention relates to a BTG2 protein and a method of producing the BTG2 protein. The BTG2 protein expressed by the vector according to the present invention binds an HA tag at its C-terminus and synthesizes two proteins to form a BTG2 protein complex. Since the BTG2 protein is not bound to the ubiquitin protein, it can be stably expressed in the cell without degrading into the 26S proteasome complex.
Description
본 발명은 세포내에서 안정성이 증가된 재조합 BTG2 단백질 및 이의 생산방법에 관한 것이다.The present invention relates to a recombinant BTG2 protein having increased stability in a cell and a production method thereof.
세포내 단백질 분해 역할을 하는 유비퀴틴-프로테아좀 시스템에서 유비퀴틴은 수명이 다한 단백질에 달라붙어 단백질 분해과정에 참여하는 인체 내 단백질이고 프로테아좀은 실제 단백질을 분해하는 효소이다. 유비퀴틴은 수명이 다한 단백질에 꼬리표처럼 달라붙어 단백질 분해효소인 프로테아좀으로 이동한 뒤 프로테아좀이 단백질을 분해시킨다. 이후 유비퀴틴은 떨어져 나와 다시 똑같은 역할을 되풀이 함으로써 세포내 항상성을 유지하고 세포의 운명을 조절하는 신호기전이다. In the ubiquitin-proteasome system, which plays a role in intracellular proteolysis, ubiquitin is a protein in the human body that attaches to the end of life protein and is involved in the proteolytic process. Proteasome is the enzyme that degrades the actual protein. Ubiquitin sticks like a tag to a protein that has reached the end of its life, then it moves to proteinase, a proteasome, and proteasome decomposes the protein. Ubiquitin then breaks apart and repeats the same role again to maintain intracellular homeostasis and regulate cell fate.
BTG 패밀리의 유전자들은 성장억제 유전자 패밀리에 속하며, BTG2(B cell translocation gene 2)는 BTG 패밀리의 구성원으로서, 다양한 암세포에서 종양억제 유전자로 보고되어 있으며, 전립선암 및 투명세포형 신세포암에서 항암효과를 나타내는 것으로 알려졌다.The BTG family of genes belongs to the family of growth inhibitory genes. BTG2 (B cell translocation gene 2) is a member of the BTG family and has been reported as a tumor suppressor gene in various cancer cells. In the prostate cancer and clear cell type neoplasms, .
또한, BTG2는 세포주기 조절, 배발달, 전사 공동-조절, 신경 분화 인자 및 내재적 세포 사멸 조절에 있어서 중요한 역할을 하고 있으며, 최근 혈당을 조절하는 대사유전자로서의 기능도 밝혀지고 있다. In addition, BTG2 plays an important role in regulation of cell cycle, embryonic development, transcriptional co-regulation, neurogenesis and intrinsic apoptosis.
이러한 BTG2는 유비퀴틴화에 의해 26S 단백질분해효소 복합체(26S proteasome complex)에 의해 분해되는 짧은 수명의 단백질로 정상세포에서는 높게 발현되지만, 다양한 암세포에서는 하향조절된다.BTG2 is a short-lived protein that is degraded by the 26S proteasome complex by ubiquitination, which is highly expressed in normal cells but down-regulated in various cancer cells.
따라서, 종양억제 유전자로 알려진 BTG2 단백질을 단백질분해효소로부터 안정적으로 세포내에 발현시키기 위한 연구가 필요한 실정이다. Therefore, there is a need for studies to stably express BTG2 protein, which is known as a tumor suppressor gene, from protease in cells.
본 발명은 세포내에서 유비퀴틴화되어 26S 단백질분해효소 복합체(26S proteasome complex)에 의해 분해되는 짧은 수명의 BTG2(B cell translocation gene 2) 단백질을 세포내에서 안정적으로 발현시키기 위한 방법을 제공하고자 한다.The present invention provides a method for stably expressing a short-lived BTG2 (B cell translational gene 2) protein, which is degraded by a 26S proteasome complex in a cell by ubiquitination.
본 발명은 서열번호 1로 표시되는 아미노산 서열을 코딩하는 BTG2 유전자 및 상기 유전자의 C-말단에 태깅된 헤마글루티닌(hemagglutinin; HA)을 코딩하는 유전자를 포함하는 재조합 벡터를 제공한다.The present invention provides a recombinant vector comprising a gene coding for the amino acid sequence of SEQ ID NO: 1 and a gene coding for hemagglutinin (HA) tagged at the C-terminal of the gene.
본 발명은 상기 재조합 벡터로 형질전환된 재조합 미생물을 제공한다.The present invention provides a recombinant microorganism transformed with said recombinant vector.
본 발명은 상기 재조합 미생물을 배양하여 BTG2-HA 재조합 단백질을 발현시키는 단계; 및 상기 BTG2-HA 재조합 단백질을 회수하는 단계를 포함하는 BTG2-HA 재조합 단백질의 생산방법을 제공한다.The present invention provides a method for producing a recombinant microorganism, which comprises culturing the recombinant microorganism to express a BTG2-HA recombinant protein; And recovering the BTG2-HA recombinant protein. The present invention also provides a method for producing BTG2-HA recombinant protein.
본 발명은 상기 재조합 단백질의 생산방법 따라 제조되며, BTG2 단백질을 안정화시킨 것을 특징으로 하는 BTG2-HA 재조합 단백질을 제공한다.The present invention provides a recombinant protein of BTG2-HA, which is prepared according to the production method of the recombinant protein and stabilizes the BTG2 protein.
또한, 본 발명은 상기 재조합 단백질의 생산방법에 따른 BTG2-HA 재조합 단백질을 유효성분으로 함유하는 항암 조성물을 제공한다.In addition, the present invention provides an anticancer composition comprising, as an active ingredient, a recombinant protein of BTG2-HA according to the production method of the recombinant protein.
본 발명에 따른 BTG2를 코딩하는 유전자와 상기 유전자의 C-말단에 태깅된 헤마글루티닌(hemagglutinin; HA)을 코딩하는 유전자를 포함한 벡터로 발현된 BTG2-HA 단백질은 C-말단에 HA-태그(tag)가 결합되며, 두 개의 단백질이 합성되어 복합체를 형성한다. 이러한 BTG2-HA 단백질은 유비퀴틴 단백질과 결합되지 않으므로 26S 단백질분해효소 복합체(26S proteasome complex)에 의해 분해되지 않고 세포내에서 안정적으로 발현될 수 있기 때문에 항암제로서 유용하게 이용될 수 있다.The BTG2-HA protein expressed in the vector containing the gene coding for BTG2 according to the present invention and the gene coding for the hemagglutinin (HA) tagged at the C-terminal of the gene has HA-tag (tag), and two proteins are synthesized to form a complex. Since the BTG2-HA protein is not bound to the ubiquitin protein, the BTG2-HA protein can be stably expressed in the cell without being degraded by the 26S proteasome complex, and thus can be useful as an anticancer agent.
도 1은 BTG2와 헤마글루티닌(hemagglutinin; HA)을 코딩하는 유전자가 포함된 pcDNA3-HA 벡터의 개열지도이다.
도 2는 293TN 세포에 BTG2가 삽입된 pcDNA3-HA 벡터 및 nV5-DEST 벡터를 처리하고 26S 단백질분해효소 억제제 MG132 처리 여부에 따라 발현된 BTG2 -HA 및 V5-BTG2 단백질의 발현량을 확인한 결과이다.
도 3은 유비퀴틴과 BTG2-HA 및 V5-BTG2 단백질의 결합 여부를 확인한 면역침전법 결과이다.1 is a cleavage map of a pcDNA3-HA vector containing a gene encoding BTG2 and hemagglutinin (HA).
FIG. 2 shows the results of the expression of BTG2-HA and V5-BTG2 proteins expressed by treatment with pcDNA3-HA vector and nV5-DEST vector in which 29GTN cells were treated with BTG2 and treated with 26S protease inhibitor MG132.
Fig. 3 is a result of immunoprecipitation method confirming the binding of ubiquitin to BTG2-HA and V5-BTG2 protein.
본 발명은 서열번호 1로 표시되는 아미노산 서열을 코팅하는 BTG2 유전자 및 상기 유전자의 C-말단에 태깅된 헤마글루티닌(hemagglutinin; HA)을 코딩하는 유전자를 포함하는 재조합 벡터를 제공한다.The present invention provides a recombinant vector comprising a gene encoding BTG2 gene that coats the amino acid sequence represented by SEQ ID NO: 1 and a hemagglutinin (HA) tagged at the C-terminal of the gene.
보다 상세하게는 상기 재조합 벡터는 도 1로 표시되는 개열지도를 갖을 수 있으며, 상기 헤마글루티닌(hemagglutinin; HA) 유전자는 서열번호 2로 표시되는 아미노산 서열로 표시될 수 있으며, 상기 BTG2 유전자는 사람 또는 마우스에서 유래될 수 있다.More specifically, the recombinant vector may have a cleavage map shown in FIG. 1, the hemagglutinin (HA) gene may be represented by the amino acid sequence shown in SEQ ID NO: 2, and the BTG2 gene Can be derived from human or mouse.
본 발명은 상기 재조합 벡터로 형질전환된 재조합 미생물을 제공할 수 있으며, 상기 재조합 미생물은 대장균일 수 있으나, 이에 한정되는 것은 아니다. The present invention may provide a recombinant microorganism transformed with the recombinant vector, and the recombinant microorganism may be E. coli, but is not limited thereto.
본 발명은 상기 재조합 미생물을 배양하여 BTG2-HA 재조합 단백질을 발현시키는 단계; 및 상기 BTG2-HA 재조합 단백질을 회수하는 단계를 포함하는 BTG2-HA 재조합 단백질의 생산방법을 제공할 수 있다.The present invention provides a method for producing a recombinant microorganism, which comprises culturing the recombinant microorganism to express a BTG2-HA recombinant protein; And recovering the BTG2-HA recombinant protein. The present invention also provides a method for producing a BTG2-HA recombinant protein.
본 발명에 따른 BTG2-HA 재조합 단백질은 서열번호 3으로 표시되는 아미노산 서열을 갖는 단백질과 서열번호 4로 표시되는 아미노산 서열을 갖는 단백질이 혼합하여 발현될 수 있으며, 상기 BTG2-HA 재조합 단백질은 BTG2 단백질을 안정화시킨 것일 수 있다.The BTG2-HA recombinant protein according to the present invention may be mixed with a protein having the amino acid sequence shown in SEQ ID NO: 3 and a protein having the amino acid sequence shown in SEQ ID NO: 4, and the BTG2- May be stabilized.
본 발명의 일실시예에 따르면, 도 2와 같이 BTG2 유전자가 삽입된 pcDNA3-HA 벡터에서 발현된 BTG2-HA 단백질은 26S 단백질분해효소 억제제인 MG132처리 여부와 상관없이 BTG2가 안정적으로 발현된 반면, BTG2 유전자가 삽입된 nV5-DEST 벡터에서 발현된 V5-BTG2 단백질은 26S 단백질분해효소 억제제인 MG132가 처리된 실험군에서만 BTG2가 발현된 것을 확인할 수 있었다.As shown in FIG. 2, the BTG2-HA protein expressed in the pcDNA3-HA vector having the BTG2 gene was stably expressed regardless of whether the 26S protease inhibitor MG132 was treated or not, The V5-BTG2 protein expressed in the nV5-DEST vector containing the BTG2 gene was confirmed to express BTG2 only in the MG132-treated group, which is a 26S protease inhibitor.
또한, 본 발명의 다른 일실시예에 따르면, 도 3과 같이 BTG2-HA 단백질의 경우, 유비퀴틴이 결합된 BTG2-HA 단백질은 나타나지 않은 반면, MG132가 처리된 V5-BTG2 단백질에서는 유비퀴틴이 결합된 V5-BTG2 단백질이 확인되었다.In addition, according to another embodiment of the present invention, as shown in FIG. 3, the BTG2-HA protein does not show ubiquitin-bound BTG2-HA protein whereas the MG132-treated V5-BTG2 protein does not show ubiquitin- -BTG2 protein was identified.
상기 결과로부터, V5-BTG2 단백질은 유비퀴틴 결합에 따른 유비퀴틴화에 의해 단백질 분해가 이루어질 수 있음이 확인된 반면, BTG2-HA 단백질은 유비퀴틴과 결합하지 않는 것이 확인됨에 따라, 본 발명의 BTG2-HA 단백질은 세포내에서 안정적으로 BTG2가 발현할 수 있음이 확인되었다.From the above results, it was confirmed that the protein degradation of V5-BTG2 protein by ubiquitin-binding was confirmed, whereas the BTG2-HA protein was found not to bind with ubiquitin, Was able to stably express BTG2 in the cells.
따라서, 본 발명은 상기 BTG2-HA 재조합 단백질을 유효성분으로 함유하는 항암 조성물로 제공될 수 있다.Accordingly, the present invention can be provided as an anticancer composition containing the BTG2-HA recombinant protein as an active ingredient.
보다 상세하게는 상기 BTG2-HA 재조합 단백질을 유효성분으로 함유하는 항암 조성물은 약학조성물로 제공될 수 있다.More particularly, the anticancer composition containing the BTG2-HA recombinant protein as an active ingredient can be provided as a pharmaceutical composition.
본 발명의 한 구체예에서, 상기 약학조성물은 통상적인 방법에 따라 주사제, 과립제, 산제, 정제, 환제, 캡슐제, 좌제, 겔, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택된 어느 하나의 제형을 사용할 수 있다.In one embodiment of the present invention, the pharmaceutical composition may be administered orally or parenterally in any conventional manner selected from the group consisting of injections, granules, powders, tablets, pills, capsules, suppositories, gels, suspensions, emulsions, Can be used.
본 발명의 다른 구체예에서, 상기 약학조성물은 약학조성물의 제조에 통상적으로 사용하는 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.In other embodiments of the present invention, the pharmaceutical compositions may be formulated with suitable carriers, excipients, disintegrants, sweeteners, coatings, swelling agents, lubricants, lubricants, flavors, antioxidants, buffers , At least one additive selected from the group consisting of a bacteriostatic agent, a diluent, a dispersant, a surfactant, a binder and a lubricant.
구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.
본 발명의 일실시예에 따르면 상기 약학조성물은 정맥내, 동맥내, 복강내, 근육내, 동맥내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.According to one embodiment of the present invention, the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.
상기 BTG2-HA 재조합 단백질의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 200 mg/kg, 구체적으로는 0.1 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.The preferable dosage of the BTG2-HA recombinant protein may vary depending on the condition and body weight of the subject, the type and degree of disease, the drug form, the administration route and the period, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.
다른 구체예로 상기 BTG2-HA 재조합 단백질을 유효성분으로 함유하는 항암 조성물은 건강식품으로 제공될 수 있다.In another embodiment, the anticancer composition containing the BTG2-HA recombinant protein as an active ingredient may be provided as a health food.
상기 건강식품은 분말, 과립, 정제, 캡슐, 시럽 또는 음료의 형태로 제공될 수 있으며, 상기 건강식품은 유효성분인 본 발명에 따른 플라스마로젠 또는 이의 유사체 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다. The health food may be provided in the form of a powder, a granule, a tablet, a capsule, a syrup or a drink. The health food is used together with food or food additives other than the plasma rosin or its analogue according to the present invention, Can be suitably used according to the method of The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.
상기 건강식품에 함유된 BTG2-HA 재조합 단백질의 유효용량은 상기 약학조성물의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the BTG2-HA recombinant protein contained in the above-mentioned health food may be used in accordance with the effective dose of the pharmaceutical composition. However, in the case of long-term ingestion for health and hygiene purposes or for health control purposes, And the active ingredient can be used in an amount of more than the above range because there is no problem in terms of safety.
상기 건강식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 들 수 있다.
There is no particular limitation on the type of the health food, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.
BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
<< 실시예Example 1> 1> 이중가닥Double strand BTG2BTG2 단백질 제조 Protein manufacture
1. 플라스미드 1. Plasmid DNADNA 구축 build
서열번호 1과 같은 아미노산 서열을 코딩하는 사람 BTG2 유전자를 PCR로 증폭 후, pcDNA3 벡터(Invitrogen) 내 제한효소 XhoΙ과 Xba Ι 사이에 헤마글루티닌(hemagglutinin; HA)을 발현시키는 DNA 단편을 삽입한 pcDNA3-HA 벡터와 nV5-DEST 벡터(Invitrogen)에 삽입하여 플라스미드 DNA를 구축하였다.A human BTG2 gene coding for the amino acid sequence as shown in SEQ ID NO: 1 was amplified by PCR, and a DNA fragment for expressing hemagglutinin (HA) was inserted between the restriction enzymes XhoI and XbaI in the pcDNA3 vector (Invitrogen) and inserted into pcDNA3-HA vector and nV5-DEST vector (Invitrogen) to construct plasmid DNA.
2. 단백질 추출 및 정제2. Protein extraction and purification
상기 두 플라스미드 DNA를 대장균(E.coli)인 DH5a(intron)에 각각 접종하여 배양한 후, GeneAll Exfection Plasmid midi kit(진올)를 이용하여 BTG2 플라스미드 DNA를 추출하였다.The two plasmid DNAs were inoculated into E. coli, DH5a (intron), and then BTG2 plasmid DNA was extracted using GeneAll Exfection Plasmid midi kit (genol).
3. 3. BTG2BTG2 단백질 확인 Protein identification
상기 추출된 BTG2 단백질을 확인한 결과, BTG2 유전자가 삽입된 pcDNA3-HA 플라스미드로 형성된 BTG2 단백질(BTG2-HA)은 C-말단에 서열번호 2와 같은 HA-태그(Pro Tyr Asp Val Pro Asp Tyr Ala)가 추가적으로 삽입되었으며, BTG2 유전자가 삽입된 V5-DEST 플라스미드로 형성된 BTG2 단백질(V5-BTG2)은 서열번호 5와 같이 N-말단에 V5-태그(Met Gly Lys Pro Ile Pro Asn Pro Leu Leu Gly Leu Asp Ser Thr)가 삽입되었으며, TEV 인식부위에 Glu Asn Leu Tyr Phe Gln Gly가 추가적으로 삽입되었으며, 아미노산(Pro Asp Pro Ser Thr Asn Ser Ala Asp Ile Thr Ser Leu Tyr Lys Lys Ala Gly Leu)이 추가적으로 삽입된 것을 확인할 수 있었다.(BTG2-HA), which was formed by the pcDNA3-HA plasmid into which the BTG2 gene was inserted, was added to the HA-tag (Pro-Tyr Asp Val Pro Asp Tyr Ala) The BTG2 protein (V5-BTG2), which was formed from the V5-DEST plasmid in which the BTG2 gene was inserted, was inserted into the V5-tag (Met Gly Lys Pro Ile Pro Asn Pro Leu Leu Gly Leu Asp Ser Thr) was inserted, Glu Asn Leu Tyr Phe Gln Gly was additionally inserted in the TEV recognition site, and amino acid (Pro Asp Pro Ser Thr Asn Ser Ala Asp Ile Thr Ser Leu Tyr Lys Lys Ala Gly Leu) was additionally inserted I could confirm.
또한, V5-BTG2 단백질은 하나의 단백질로 합성된 반면, BTG2-HA 단백질은 서열번호 3 및 서열번호 4의 아미노산으로 표시되는 두 개의 단백질이 혼합되어 BTG2-HA 단백질 복합체를 형성하는 것으로 확인되었다.
In addition, it was confirmed that the V5-BTG2 protein was synthesized as one protein while the BTG2-HA protein was a mixture of two proteins represented by amino acids of SEQ ID NO: 3 and SEQ ID NO: 4 to form a BTG2-HA protein complex.
<< 실시예Example 2> 2> BTG2BTG2 단백질 안정성 확인 Confirm protein stability
1. One. BTG2BTG2 단백질의 과발현 유도 Induction of protein overexpression
100 mm 배양접시에 293TN 세포(ATCC)를 배양하고 70-80% 존재할 때, 지질을 이용한 Lipofector-EZ transfection reagent(Aptabio)를 이용하여 BTG2-HA 단백질 발현 벡터 및 V5-BTG2 단백질 발현 벡터를 각각 0, 1 및 2μg으로 처리하고 21시간 동안 인큐베이션하였다.When the 293TN cells (ATCC) were cultured in a 100-mm culture dish, the BTG2-HA protein expression vector and the V5-BTG2 protein expression vector were expressed as 0 , 1 and 2 [mu] g, and incubated for 21 hours.
그 후, 26S 단백질분해효소 억제제인 MG132(Sigma)를 5μM 처리하고 3시간 후 293TN 세포를 수집하여 단백질을 추출하였다.Then, MG132 (Sigma), a 26S protease inhibitor, was treated at 5 μM, and 3 hours later, 293TN cells were collected and proteins were extracted.
단백질 추출에 사용된 추출버퍼는 25mM 헵스(Hepes; pH 7.6), 1mM EDTA, 1.5mM NaCl, 1% 트리톤 X-100 상태로 제조하였고, 단백질을 추출하기 바로 직전에 프로티아제 억제제 혼합물(Biovision)과 포스파티아제 억제제 혼합물(Biovision)을 혼합하여 사용하였다. The extraction buffer used for protein extraction was prepared with 25 mM Hepes (pH 7.6), 1 mM EDTA, 1.5 mM NaCl and 1% Triton X-100. Just prior to protein extraction, the protease inhibitor mixture (Biovision) And a phosphatase inhibitor mixture (Biovision) were mixed and used.
2. 2. BTG2BTG2 단백질 발현량 확인 Confirm protein expression level
상기 추출된 단백질에서 면역블로팅(immunoblotting; IB) 방법으로 BTG2 단백질 발현량을 확인하였다. 아크릴아마이드 겔(acrylamid gel; 노블바이오)을 이용하여 추출된 BTG2 단백질을 전기영동한 후, 니트로셀룰로스 막(nitrocellulose membrane; 밀리포어)으로 옮긴 후 HA(Santa Cruz), α-튜불린(Santa Cruz) 및 V5(Novus) 항체를 이용하여 BTG2 단백질 발현량을 확인하였다.The expression level of BTG2 protein was confirmed by immunoblotting (IB) in the extracted proteins. BTG2 protein extracted using acrylamide gel was transferred to a nitrocellulose membrane (Millipore), and then HA (Santa Cruz), α-tubulin (Santa Cruz) And V5 (Novus) antibody were used to confirm the expression level of BTG2 protein.
그 결과, 도 2와 같이 V5-BTG2 단백질은 26S 단백질분해효소 억제제인 MG132을 처리한 경우, 약하게 검출되었던 V5-BTG2 단백질의 발현량이 매우 증가한 반면, BTG2-HA 단백질의 경우, MG132 처리 여부와 상관없이 안정적으로 단백질이 발현되는 것을 확인할 수 있었다.As a result, as shown in FIG. 2, when the 26S protease inhibitor MG132 was treated with V5-BTG2 protein, the expression level of V5-BTG2 protein, which was weakly detected, was greatly increased, whereas the BTG2- The protein was stably expressed in the absence of the enzyme.
상기 결과로부터 BTG2-HA 단백질이 26S 단백질분해효소 존재하에서도 안정적으로 발현되는 것이 확인되었다.From the above results, it was confirmed that BTG2-HA protein was stably expressed even in the presence of 26S protease.
3. 3. BTG2BTG2 단백질의 Protein 유비퀴틴화Ubiquitination 확인 Confirm
BTG2-HA 단백질 및 V5-BTG2 단백질의 유비퀴틴화 여부를 확인하기 위해, 상기 방법으로 준비된 BTG2-HA 단백질 및 V5-BTG2 단백질에 유비퀴틴(ubiquitin) 항체와 재조합 단백질 G 비드(인코스팜)을 이용한 면역침전실험(immunoprecipitation)을 수행하여, 유비퀴틴이 결합된 단백질을 침전시켜 각 BTG2 단백질과 유비퀴틴 결합 여부를 확인하였다. In order to confirm the ubiquitination of the BTG2-HA protein and the V5-BTG2 protein, the BTG2-HA protein and the V5-BTG2 protein prepared by the above method were subjected to immune precipitation using a ubiquitin antibody and a recombinant protein G bead (incose palm) Immunoprecipitation was performed to confirm the binding of ubiquitin to each BTG2 protein by precipitating the protein bound to ubiquitin.
그 결과 도 3과 같이, BTG2-HA 단백질의 경우, MG132 처리 여부와 상관없이 유비퀴틴이 결합된 BTG2-HA 단백질의 밴드가 나타나지 않은 반면, MG132가 처리된 V5-BTG2 단백질에서는 유비퀴틴이 결합된 V5-BTG2 단백질 밴드가 확인되었다.As a result, as shown in FIG. 3, the BTG2-HA protein did not show a band of BTG2-HA protein bound with ubiquitin regardless of treatment with MG132, whereas in MG132-treated V5-BTG2 protein, the ubiquitin- The BTG2 protein band was identified.
상기 결과로부터, V5-BTG2 단백질은 유비퀴틴 결합에 따른 유비퀴틴화에 의한 단백질 분해가 이루어질 수 있음이 확인된 반면, BTG2-HA 단백질은 유비퀴틴과 결합하지 않는 것이 확인되었다.From the above results, it was confirmed that the V5-BTG2 protein can be degraded by ubiquitination due to ubiquitin binding, while the BTG2-HA protein does not bind with ubiquitin.
상기 결과로부터 본 발명에 따른 BTG2-HA 단백질은 유비퀴틴 단백질과 결합되지 않으므로, 26S 단백질분해효소 복합체(26S proteasome complex)에 분해되지 않고 세포내에서 안정적으로 발현되는 것이 확인되었다.
From the above results, it was confirmed that the BTG2-HA protein according to the present invention is not bound to the ubiquitin protein, and thus is stably expressed in the cell without degrading into the 26S proteasome complex.
이하, 본 발명의 약학조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, formulation examples of the pharmaceutical composition of the present invention will be described, but the present invention is not intended to be limited thereto but is specifically explained.
<< 제제예Formulation example 1> 주사제의 제조 1> Preparation of injection
BTG2-HA 10 mg, 소디움 메타비설파이트 3.0 mg, 메틸파라벤 0.8 mg, 프로필파라벤 0.1 mg 및 주사용 멸균증류수 적량을 혼합하고 통상의 방법으로 최종 부피가 2 ㎖이 되도록 제조한 후, 2 ㎖ 용량의 앰플에 충전하고 멸균하여 주사제를 제조하였다.10 mg of BTG2-HA, 3.0 mg of sodium metabisulfite, 0.8 mg of methylparaben, 0.1 mg of propylparaben and an appropriate amount of sterilized distilled water for injection were mixed and made to a final volume of 2 ml by a conventional method, The ampoules were filled and sterilized to prepare an injection.
<< 제제예Formulation example 2> 정제의 제조 2> Preparation of tablets
BTG2-HA 10 mg, 유당 100 mg, 전분 100 mg 및 스테아린산 마그네슘 적량을 혼합하고 통상의 정제 제조방법에 따라 타정하여 정제를 제조하였다.10 mg of BTG2-HA, 100 mg of lactose, 100 mg of starch and an appropriate amount of magnesium stearate, and tableted according to a conventional tablet preparation method.
<제제예 3> 캡슐제의 제조≪ Formulation Example 3 > Preparation of capsules
BTG2-HA 10 mg, 유당 50 ㎎, 전분 50 ㎎, 탈크 2 ㎎ 및 스테아린산 마그네슘 적량을 혼합하고 통상의 캡슐제 제조방법에 따라 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.
10 mg of BTG2-HA, 50 mg of lactose, 50 mg of starch, 2 mg of talc, and an appropriate amount of magnesium stearate were mixed and filled in gelatin capsules according to a conventional capsule preparation method to prepare capsules.
이하, 본 발명에 따른 BTG2-HA를 이용한 건강식품 제조예를 설명하나, 이는 본 발명을 한정하고자 함이 아니라 단지 구체적으로 설명하고자 함이다.Hereinafter, a production example of health food using BTG2-HA according to the present invention will be described, but it is not intended to limit the present invention, but is to be specifically described.
<< 제조예Manufacturing example 1> 건강식품의 제조 1> Manufacture of health food
BTG2-HA 10mg, 비타민 혼합물 적량(비타민 A 아세테이트 70 ㎍, 비타민 E 1.0 ㎎, 비타민 B 1 0.13 ㎎, 비타민 B 2 0.15 ㎎, 비타민 B 6 0.5 ㎎, 비타민 B 12 0.2 ㎍, 비타민 C 10 ㎎, 비오틴 10 ㎍, 니코틴산아미드 1.7 ㎎, 엽산 50 ㎍, 판토텐산 칼슘 0.5 ㎎), 무기질 혼합물 적량(황산제1철 1.75 ㎎, 산화아연 0.82 ㎎, 탄산마그네슘 25.3 ㎎, 제1인산칼륨 15 ㎎, 제2인산칼슘 55 ㎎, 구연산칼륨 90 ㎎, 탄산칼슘 100 ㎎, 염화마그네슘 24.8 ㎎)을 혼합한 다음 과립을 제조하고 통상의 방법에 따라 건강식품을 제조하였다.BTG2-
<< 제조예Manufacturing example 2> 2> 건강음료의Health drink 제조 Produce
BTG2-HA 10mg, 구연산 1000 ㎎, 올리고당 100 g, 매실농축액 2 g, 타우린 1 g 및 정제수를 가하여 전체 900 ㎖가 되도록 하며, 통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관하였다.
BTG2-HA, 1000 mg of citric acid, 100 g of oligosaccharide, 2 g of plum concentrate, 1 g of taurine and purified water were added to make a total of 900 ml, and the above components were mixed according to a conventional health drink manufacturing method, After stirring and heating at 85 ° C for a period of time, the resulting solution was filtered and sterilized by sealing in a 2 L container which was then sterilized and then refrigerated.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.
While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
<110> AJOU UNIVERSITY INDUSTRY-ACADEMIC COOPERATION FOUNDATION <120> Recombinant BTG2 protein and production method thereof <130> ADP-2015-0059 <160> 5 <170> KopatentIn 2.0 <210> 1 <211> 158 <212> PRT <213> BTG2 <400> 1 Met Ser His Gly Lys Gly Thr Asp Met Leu Pro Glu Ile Ala Ala Ala 1 5 10 15 Val Gly Phe Leu Ser Ser Leu Leu Arg Thr Arg Gly Cys Val Ser Glu 20 25 30 Gln Arg Leu Lys Val Phe Ser Gly Ala Leu Gln Glu Ala Leu Thr Glu 35 40 45 His Tyr Lys His His Trp Phe Pro Glu Lys Pro Ser Lys Gly Ser Gly 50 55 60 Tyr Arg Cys Ile Arg Ile Asn His Lys Met Asp Pro Ile Ile Ser Arg 65 70 75 80 Val Ala Ser Gln Ile Gly Leu Ser Gln Pro Gln Leu His Gln Leu Leu 85 90 95 Pro Ser Glu Leu Thr Leu Trp Val Asp Pro Tyr Glu Val Ser Tyr Arg 100 105 110 Ile Gly Glu Asp Gly Ser Ile Cys Val Leu Tyr Glu Glu Ala Pro Leu 115 120 125 Ala Ala Ser Cys Gly Leu Leu Thr Cys Lys Asn Gln Val Leu Leu Gly 130 135 140 Arg Ser Ser Pro Ser Lys Asn Tyr Val Met Ala Val Ser Ser 145 150 155 <210> 2 <211> 9 <212> PRT <213> HA tag <400> 2 Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1 5 <210> 3 <211> 172 <212> PRT <213> BTG2-HA <400> 3 Met Ser His Gly Lys Gly Thr Asp Met Leu Pro Glu Ile Ala Ala Ala 1 5 10 15 Val Gly Phe Leu Ser Ser Leu Leu Arg Thr Arg Gly Cys Val Ser Glu 20 25 30 Gln Arg Leu Lys Val Phe Ser Gly Ala Leu Gln Glu Ala Leu Thr Glu 35 40 45 His Tyr Lys His His Trp Phe Pro Glu Lys Pro Ser Lys Gly Ser Gly 50 55 60 Tyr Arg Cys Ile Arg Ile Asn His Lys Met Asp Pro Ile Ile Ser Arg 65 70 75 80 Val Ala Ser Gln Ile Gly Leu Ser Gln Pro Gln Leu His Gln Leu Leu 85 90 95 Pro Ser Glu Leu Thr Leu Trp Val Asp Pro Tyr Glu Val Ser Tyr Arg 100 105 110 Ile Gly Glu Asp Gly Ser Ile Cys Val Leu Tyr Glu Glu Ala Pro Leu 115 120 125 Ala Ala Ser Cys Gly Leu Leu Thr Cys Lys Asn Gln Val Leu Leu Gly 130 135 140 Arg Ser Ser Pro Ser Lys Asn Tyr Val Met Ala Val Ser Ser Leu Glu 145 150 155 160 Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Ser Leu 165 170 <210> 4 <211> 164 <212> PRT <213> BTG2-HA <400> 4 Met Leu Pro Glu Ile Ala Ala Ala Val Gly Phe Leu Ser Ser Leu Leu 1 5 10 15 Arg Thr Arg Gly Cys Val Ser Glu Gln Arg Leu Lys Val Phe Ser Gly 20 25 30 Ala Leu Gln Glu Ala Leu Thr Glu His Tyr Lys His His Trp Phe Pro 35 40 45 Glu Lys Pro Ser Lys Gly Ser Gly Tyr Arg Cys Ile Arg Ile Asn His 50 55 60 Lys Met Asp Pro Ile Ile Ser Arg Val Ala Ser Gln Ile Gly Leu Ser 65 70 75 80 Gln Pro Gln Leu His Gln Leu Leu Pro Ser Glu Leu Thr Leu Trp Val 85 90 95 Asp Pro Tyr Glu Val Ser Tyr Arg Ile Gly Glu Asp Gly Ser Ile Cys 100 105 110 Val Leu Tyr Glu Glu Ala Pro Leu Ala Ala Ser Cys Gly Leu Leu Thr 115 120 125 Cys Lys Asn Gln Val Leu Leu Gly Arg Ser Ser Pro Ser Lys Asn Tyr 130 135 140 Val Met Ala Val Ser Ser Leu Glu Gly Tyr Pro Tyr Asp Val Pro Asp 145 150 155 160 Tyr Ala Ser Leu <210> 5 <211> 199 <212> PRT <213> V5-BTG2 <400> 5 Met Gly Lys Pro Ile Pro Asn Pro Leu Leu Gly Leu Asp Ser Thr Glu 1 5 10 15 Asn Leu Tyr Phe Gln Gly Pro Asp Pro Ser Thr Asn Ser Ala Asp Ile 20 25 30 Thr Ser Leu Tyr Lys Lys Ala Gly Leu Met Ser His Gly Lys Gly Thr 35 40 45 Asp Met Leu Pro Glu Ile Ala Ala Ala Val Gly Phe Leu Ser Ser Leu 50 55 60 Leu Arg Thr Arg Gly Cys Val Ser Glu Gln Arg Leu Lys Val Phe Ser 65 70 75 80 Gly Ala Leu Gln Glu Ala Leu Thr Glu His Tyr Lys His His Trp Phe 85 90 95 Pro Glu Lys Pro Ser Lys Gly Ser Gly Tyr Arg Cys Ile Arg Ile Asn 100 105 110 His Lys Met Asp Pro Ile Ile Ser Arg Val Ala Ser Gln Ile Gly Leu 115 120 125 Ser Gln Pro Gln Leu His Gln Leu Leu Pro Ser Glu Leu Thr Leu Trp 130 135 140 Val Asp Pro Tyr Glu Val Ser Tyr Arg Ile Gly Glu Asp Gly Ser Ile 145 150 155 160 Cys Val Leu Tyr Glu Glu Ala Pro Leu Ala Ala Ser Cys Gly Leu Leu 165 170 175 Thr Cys Lys Asn Gln Val Leu Leu Gly Arg Ser Ser Pro Ser Lys Asn 180 185 190 Tyr Val Met Ala Val Ser Ser 195 <110> AJOU UNIVERSITY INDUSTRY-ACADEMIC COOPERATION FOUNDATION <120> Recombinant BTG2 protein and production method thereof <130> ADP-2015-0059 <160> 5 <170> Kopatentin 2.0 <210> 1 <211> 158 <212> PRT <213> BTG2 <400> 1 Met Ser His Gly Lys Gly Thr Asp Met Leu Pro Glu Ile Ala Ala Ala 1 5 10 15 Val Gly Phe Leu Ser Ser Leu Leu Arg Thr Arg Gly Cys Val Ser Glu 20 25 30 Gln Arg Leu Lys Val Phe Ser Gly Ala Leu Gln Glu Ala Leu Thr Glu 35 40 45 His Tyr Lys His His Trp Phe Pro Glu Lys Pro Ser Lys Gly Ser Gly 50 55 60 Tyr Arg Cys Ile Arg Ile Asn His Lys Met Asp Pro Ile Ile Ser Arg 65 70 75 80 Val Ala Ser Gln Ile Gly Leu Ser Gln Pro Gln Leu His Gln Leu Leu 85 90 95 Pro Ser Glu Leu Thr Leu Trp Val Asp Pro Tyr Glu Val Ser Tyr Arg 100 105 110 Ile Gly Glu Asp Gly Ser Ile Cys Val Leu Tyr Glu Glu Ala Pro Leu 115 120 125 Ala Ala Ser Cys Gly Leu Leu Thr Cys Lys Asn Gln Val Leu Leu Gly 130 135 140 Arg Ser Ser Pro Ser Lys Asn Tyr Val Met Ala Val Ser Ser 145 150 155 <210> 2 <211> 9 <212> PRT <213> HA tag <400> 2 Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1 5 <210> 3 <211> 172 <212> PRT <213> BTG2-HA <400> 3 Met Ser His Gly Lys Gly Thr Asp Met Leu Pro Glu Ile Ala Ala Ala 1 5 10 15 Val Gly Phe Leu Ser Ser Leu Leu Arg Thr Arg Gly Cys Val Ser Glu 20 25 30 Gln Arg Leu Lys Val Phe Ser Gly Ala Leu Gln Glu Ala Leu Thr Glu 35 40 45 His Tyr Lys His His Trp Phe Pro Glu Lys Pro Ser Lys Gly Ser Gly 50 55 60 Tyr Arg Cys Ile Arg Ile Asn His Lys Met Asp Pro Ile Ile Ser Arg 65 70 75 80 Val Ala Ser Gln Ile Gly Leu Ser Gln Pro Gln Leu His Gln Leu Leu 85 90 95 Pro Ser Glu Leu Thr Leu Trp Val Asp Pro Tyr Glu Val Ser Tyr Arg 100 105 110 Ile Gly Glu Asp Gly Ser Ile Cys Val Leu Tyr Glu Glu Ala Pro Leu 115 120 125 Ala Ala Ser Cys Gly Leu Leu Thr Cys Lys Asn Gln Val Leu Leu Gly 130 135 140 Arg Ser Ser Ser Ser Ser Ser Leu Glu 145 150 155 160 Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Ser Leu 165 170 <210> 4 <211> 164 <212> PRT <213> BTG2-HA <400> 4 Met Leu Pro Glu Ile Ala Ala Ala Val Gly Phe Leu Ser Ser Leu Leu 1 5 10 15 Arg Thr Arg Gly Cys Val Ser Glu Gln Arg Leu Lys Val Phe Ser Gly 20 25 30 Ala Leu Gln Glu Ala Leu Thr Glu His Tyr Lys His His Trp Phe Pro 35 40 45 Glu Lys Pro Ser Lys Gly Ser Gly Tyr Arg Cys Ile Arg Ile Asn His 50 55 60 Lys Met Asp Pro Ile Ile Ser Arg Val Ala Ser Gln Ile Gly Leu Ser 65 70 75 80 Gln Pro Gln Leu His Gln Leu Leu Pro Ser Glu Leu Thr Leu Trp Val 85 90 95 Asp Pro Tyr Glu Val Ser Tyr Arg Ile Gly Glu Asp Gly Ser Ile Cys 100 105 110 Val Leu Tyr Glu Glu Ala Pro Leu Ala Ala Ser Cys Gly Leu Leu Thr 115 120 125 Cys Lys Asn Gln Val Leu Leu Gly Arg Ser Ser Pro Ser Lys Asn Tyr 130 135 140 Val Met Ala Val Ser Ser Leu Glu Gly Tyr Pro Tyr Asp Val Pro Asp 145 150 155 160 Tyr Ala Ser Leu <210> 5 <211> 199 <212> PRT <213> V5-BTG2 <400> 5 Met Gly Lys Pro Ile Pro Asn Pro Leu Leu Gly Leu Asp Ser Thr Glu 1 5 10 15 Asn Leu Tyr Phe Gln Gly Pro Asp Pro Ser Thr Asn Ser Ala Asp Ile 20 25 30 Thr Ser Leu Tyr Lys Lys Ala Gly Leu Met Ser His Gly Lys Gly Thr 35 40 45 Asp Met Leu Pro Glu Ile Ala Ala Val Gly Phe Leu Ser Ser Leu 50 55 60 Leu Arg Thr Arg Gly Cys Val Ser Glu Gln Arg Leu Lys Val Phe Ser 65 70 75 80 Gly Ala Leu Gln Glu Ala Leu Thr Glu His Tyr Lys His His Trp Phe 85 90 95 Pro Glu Lys Pro Ser Lys Gly Ser Gly Tyr Arg Cys Ile Arg Ile Asn 100 105 110 His Lys Met Asp Pro Ile Ile Ser Arg Val Ala Ser Gln Ile Gly Leu 115 120 125 Ser Gln Pro Gln Leu His Gln Leu Leu Pro Ser Glu Leu Thr Leu Trp 130 135 140 Val Asp Pro Tyr Glu Val Ser Tyr Arg Ile Gly Glu Asp Gly Ser Ile 145 150 155 160 Cys Val Leu Tyr Glu Glu Ala Pro Leu Ala Ala Ser Cys Gly Leu Leu 165 170 175 Thr Cys Lys Asn Gln Val Leu Leu Gly Arg Ser Ser Ser Ser Ser Asn 180 185 190 Tyr Val Met Ala Val Ser Ser 195
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