Apoptosis Peptides
Definition
Apoptosis or programmed cell death is a normal component of the development and health of multicellular organisms. Cells die in response to a variety of stimuli and during apoptosis they do so in a controlled, regulated fashion.
Discovery
In 1885, Flemming W described the process of programmed cell death. John Kerr's discovery, in late 1960s, initially called "shrinkage necrosis" but which he later renamed "apoptosis", came about when his attention was caught by a curious form of liver cell death during his studies of acute liver injury in rats 1,2. Kerr in 1972 proposed the term apoptosis is for mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological 3.
Structural Characteristics
Heterodimerization between members of the Bcl-2 family of proteins is a key event in the regulation of programmed cell death. The molecular basis for heterodimer formation was investigated by determination of the solution structure of a complex between the survival protein Bcl-xL and the death-promoting region of the Bcl-2-related protein Bak. The structure and binding affinities of mutant Bak peptides indicate that the Bak peptide adopts an amphipathic helix that interacts with Bcl-xL through hydrophobic and electrostatic interactions. Mutations in full-length Bak that disrupt either type of interaction inhibit the ability of Bak to heterodimerize with Bcl-xL 4.
The structure of the 16-amino acid peptide complexed with a biologically active deletion mutant of Bcl-xL was determined by nuclear magnetic resonance spectroscopy (NMR). The structure was determined from a total of 2813 NMR-derived restraints and is well defined by the NMR data. The Bak peptide forms a helix when complexed to Bcl-xL. The COOH terminal portion of the Bak peptide interacts predominantly with residues in the BH2 and BH3 regions. Melanoma inhibitor of apoptosis (ML-IAP) is a potent anti-apoptotic protein that is upregulated in a number of melanoma cell lines but not expressed in most normal adult tissues. Overexpression of IAP proteins, such as ML-IAP or the ubiquitously expressed X-chromosome-linked IAP (XIAP), in human cancers has been shown to suppress apoptosis induced by a variety of stimuli. X-ray crystal structures of ML-IAP-BIR in complex with Smac- and phage-derived peptides, together with peptide structure%u2212activity-relationship data, indicate that the peptides can be modified to provide increased binding affinity and selectivity for ML-IAP-BIR relative to XIAP-BIR3 5.
Mode of Action
Upon receiving specific signals instructing the cells to undergo apoptosis a number of distinctive changes occur in the cell. Families of proteins known as caspases are typically activated in the early stages of apoptosis. These proteins breakdown or cleave key cellular components that are required for normal cellular function including structural proteins in the cytoskeleton and nuclear proteins such as DNA repair enzymes. The caspases can also activate other degradative enzymes such as DNases, which begin to cleave the DNA in the nucleus.
Apoptotic cells display distinctive morphology during the apoptotic process. Typically, the cell begins to shrink following the cleavage of lamins and actin filaments in the cytoskeleton. The breakdown of chromatin in the nucleus often leads to nuclear condensation and in many cases the nuclei of apoptotic cells take on a "horse-shoe" like appearance. Cells continue to shrink, packaging themselves into a form that allows for their removal by macrophages. There are a number of mechanisms through which apoptosis can be induced in cells. The sensitivity of cells to any of these stimuli can vary depending on a number of factors such as the expression of pro- and anti-apoptotic proteins (eg. the Bcl-2 proteins or the Inhibitor of Apoptosis Proteins), the severity of the stimulus and the stage of the cell cycle. The Bcl-2 family of proteins plays a central role in the regulation of apoptotic cell death induced by a wide variety of stimuli. Some proteins within this family, including Bcl-2 and Bcl-xL, inhibit programmed cell death, and others, such as Bax and Bak, can promote apoptosis 6, 7.
Functions
For development, Apoptosis is as needed for proper development as mitosis is. Examples: The resorption of the tadpole tail at the time of its metamorphosis into a frog occurs by apoptosis.
Integrity of the organism, Apoptosis is needed to destroy cells that represent a threat to the integrity of the organism. Examples: Cells infected with viruses8.
Cells of the immune system, as cell-mediated immune responses wane, the effector cells must be removed to prevent them from attacking body constituents. CTLs induce apoptosis in each other and even in themselves 9.
Cells with DNA damage, damage to its genome can cause a cell to disrupt proper embryonic development leading to birth defects to become cancerous.
References
1.Kerr JF (1965). A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes. Journal of Pathology and Bacteriology, 90(90):419-435.
2.Kerr JF, Wyllie AH, Currie AR (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer., 26(4):239-257.
3.O'Rourke MG, Ellem KA (2000). John Kerr and apoptosis. Med. J. Aust., 173(11-12): 616-617.
4.Franklin MC, Kadkhodayan S, Ackerly H, Alexandru D, Distefano MD, Elliott LO, Flygare JA, Mausisa G, Okawa DC, Ong D, Vucic D, Deshayes K, Fairbrother WJ (2003). Structure and function analysis of peptide antagonists of melanoma inhibitor of apoptosis (ML-IAP). Biochemistry, 42(27):8223-8231.
5.Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB, Fesik SW (1997). Structure of bcl-xl-bak peptide complex: recognition between regulators of apoptosis. Science, 275(5302):983-986.
6.Hanada M, Aimé-Sempé C, Sato T, Reed JC (1995). Structure-function analysis of Bcl-2 protein. Identification of conserved domains important for homodimerization with Bcl-2 and heterodimerization with Bax. J. Biol. Chem., 270(20):11962-11969.
7.Cheng EHY, Levine B, Boise LH, Thompson CB, Hardwic JM (1996). Bax-independent inhibition of apoptosis by Bcl-xL.Nature, 379:554-556.
8.Alimonti JB, Ball TB, Fowke KR (2003). Mechanisms of CD4 T lymphocyte cell death in human immunodeficiency virus infection and AIDS. J Gen Virology., 84(84): 1649-1661.
9.Werlen G, Hausmann B, Naeher D, Palmer E (2003). Signaling life and death in the thymus: timing is everything. Science. 299(5614):1859-1863.
Please visit our Blog on Blogspot Bio-Synthesis
Apoptosis or programmed cell death is a normal component of the development and health of multicellular organisms. Cells die in response to a variety of stimuli and during apoptosis they do so in a controlled, regulated fashion.
Discovery
In 1885, Flemming W described the process of programmed cell death. John Kerr's discovery, in late 1960s, initially called "shrinkage necrosis" but which he later renamed "apoptosis", came about when his attention was caught by a curious form of liver cell death during his studies of acute liver injury in rats 1,2. Kerr in 1972 proposed the term apoptosis is for mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological 3.
Structural Characteristics
Heterodimerization between members of the Bcl-2 family of proteins is a key event in the regulation of programmed cell death. The molecular basis for heterodimer formation was investigated by determination of the solution structure of a complex between the survival protein Bcl-xL and the death-promoting region of the Bcl-2-related protein Bak. The structure and binding affinities of mutant Bak peptides indicate that the Bak peptide adopts an amphipathic helix that interacts with Bcl-xL through hydrophobic and electrostatic interactions. Mutations in full-length Bak that disrupt either type of interaction inhibit the ability of Bak to heterodimerize with Bcl-xL 4.
The structure of the 16-amino acid peptide complexed with a biologically active deletion mutant of Bcl-xL was determined by nuclear magnetic resonance spectroscopy (NMR). The structure was determined from a total of 2813 NMR-derived restraints and is well defined by the NMR data. The Bak peptide forms a helix when complexed to Bcl-xL. The COOH terminal portion of the Bak peptide interacts predominantly with residues in the BH2 and BH3 regions. Melanoma inhibitor of apoptosis (ML-IAP) is a potent anti-apoptotic protein that is upregulated in a number of melanoma cell lines but not expressed in most normal adult tissues. Overexpression of IAP proteins, such as ML-IAP or the ubiquitously expressed X-chromosome-linked IAP (XIAP), in human cancers has been shown to suppress apoptosis induced by a variety of stimuli. X-ray crystal structures of ML-IAP-BIR in complex with Smac- and phage-derived peptides, together with peptide structure%u2212activity-relationship data, indicate that the peptides can be modified to provide increased binding affinity and selectivity for ML-IAP-BIR relative to XIAP-BIR3 5.
Mode of Action
Upon receiving specific signals instructing the cells to undergo apoptosis a number of distinctive changes occur in the cell. Families of proteins known as caspases are typically activated in the early stages of apoptosis. These proteins breakdown or cleave key cellular components that are required for normal cellular function including structural proteins in the cytoskeleton and nuclear proteins such as DNA repair enzymes. The caspases can also activate other degradative enzymes such as DNases, which begin to cleave the DNA in the nucleus.
Apoptotic cells display distinctive morphology during the apoptotic process. Typically, the cell begins to shrink following the cleavage of lamins and actin filaments in the cytoskeleton. The breakdown of chromatin in the nucleus often leads to nuclear condensation and in many cases the nuclei of apoptotic cells take on a "horse-shoe" like appearance. Cells continue to shrink, packaging themselves into a form that allows for their removal by macrophages. There are a number of mechanisms through which apoptosis can be induced in cells. The sensitivity of cells to any of these stimuli can vary depending on a number of factors such as the expression of pro- and anti-apoptotic proteins (eg. the Bcl-2 proteins or the Inhibitor of Apoptosis Proteins), the severity of the stimulus and the stage of the cell cycle. The Bcl-2 family of proteins plays a central role in the regulation of apoptotic cell death induced by a wide variety of stimuli. Some proteins within this family, including Bcl-2 and Bcl-xL, inhibit programmed cell death, and others, such as Bax and Bak, can promote apoptosis 6, 7.
Functions
For development, Apoptosis is as needed for proper development as mitosis is. Examples: The resorption of the tadpole tail at the time of its metamorphosis into a frog occurs by apoptosis.
Integrity of the organism, Apoptosis is needed to destroy cells that represent a threat to the integrity of the organism. Examples: Cells infected with viruses8.
Cells of the immune system, as cell-mediated immune responses wane, the effector cells must be removed to prevent them from attacking body constituents. CTLs induce apoptosis in each other and even in themselves 9.
Cells with DNA damage, damage to its genome can cause a cell to disrupt proper embryonic development leading to birth defects to become cancerous.
References
1.Kerr JF (1965). A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes. Journal of Pathology and Bacteriology, 90(90):419-435.
2.Kerr JF, Wyllie AH, Currie AR (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer., 26(4):239-257.
3.O'Rourke MG, Ellem KA (2000). John Kerr and apoptosis. Med. J. Aust., 173(11-12): 616-617.
4.Franklin MC, Kadkhodayan S, Ackerly H, Alexandru D, Distefano MD, Elliott LO, Flygare JA, Mausisa G, Okawa DC, Ong D, Vucic D, Deshayes K, Fairbrother WJ (2003). Structure and function analysis of peptide antagonists of melanoma inhibitor of apoptosis (ML-IAP). Biochemistry, 42(27):8223-8231.
5.Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB, Fesik SW (1997). Structure of bcl-xl-bak peptide complex: recognition between regulators of apoptosis. Science, 275(5302):983-986.
6.Hanada M, Aimé-Sempé C, Sato T, Reed JC (1995). Structure-function analysis of Bcl-2 protein. Identification of conserved domains important for homodimerization with Bcl-2 and heterodimerization with Bax. J. Biol. Chem., 270(20):11962-11969.
7.Cheng EHY, Levine B, Boise LH, Thompson CB, Hardwic JM (1996). Bax-independent inhibition of apoptosis by Bcl-xL.Nature, 379:554-556.
8.Alimonti JB, Ball TB, Fowke KR (2003). Mechanisms of CD4 T lymphocyte cell death in human immunodeficiency virus infection and AIDS. J Gen Virology., 84(84): 1649-1661.
9.Werlen G, Hausmann B, Naeher D, Palmer E (2003). Signaling life and death in the thymus: timing is everything. Science. 299(5614):1859-1863.
Please visit our Blog on Blogspot Bio-Synthesis
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BIO-SYNTHESIS, INC., is a leading life science products company with over 20 years of experience in the design and synthesis of Custom Peptide, small molecules and reagents for small scale research and bulk pharmaceutical trials. Using state of the art technology in our well-equipped laboratories.
Please visit our Blog on Blogspot Bio-Synthesis
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Founded in 1984, Bio-Synthesis, Inc. was first known as OCS Laboratories. It was the first producer of commercially available synthetic DNA and, in 1985, became a producer of synthetic peptides. In 1989, OCS incorporated as Bio-Synthesis, Inc. and moved its laboratories to Lewisville, Texas. Today, BSI occupies 10,000 square feet of modern laboratory space (completed in 1995) located 20 miles from downtown Dallas and 10 miles from D/FW airport. Among the surrounding academic institutions are: University of Texas Southwestern Medical School (12 miles), University of North Texas (10 miles), and University of North Texas Health Science Center (25 miles). These universities provide excellent library resources. Since its inception, BSI has steadily expanded its product lines and services to meet the growing needs of the molecular biology community. It has maintained its position as an aggressive, innovative company in a highly competitive marketplace without sacrificing quality. In the beginning, our primary emphasis was on synthesizing high quality DNA primers and linkers, which were the initial uses of oligos. Today, newer technologies, such as gene construction, PCR, mutagenesis, combinatorial libraries, dye/adduct labeling, DNA microarrays, peptide-nucleic acid chimeras, etc. have challenged the molecular biology field. In response, BSI has branched into several related areas including DNA paternity testing, DNA HLA typing, PNA synthesis, genomic sequencing, fluorescence-based genotyping, custom organic synthesis and other molecular biology based applications.
The Research and Development Division comprises a number of Ph.D. and M.D. professionals with backgrounds in molecular biology, immunology, nucleic acids, peptide synthesis, general organic chemistry, and automated amino acid sequencing. The Molecular Biology Division is set up to handle most modern experimental procedures; the Immunology Division specializes in immunodiagnostic-based reagents.
Not only has BSI continued to provide quality DNA products and services for the research community, but it has also become a world leader in providing custom peptide products and services. Using state-of-the-art solid phase peptide chemistries, BSI provides high quality custom peptides, performs carrier conjugations, antipeptide antibody production, antigenic peptide design, synthesis of long and/or modified peptides, MALDI TOF analysis, contract research, consultation services and more.
Biomedical researchers worldwide in universities, biotech companies, private clinics, and government agencies use products from Bio-Synthesis, Inc. in studies ranging from PCR diagnostics to cancer research and the Human Genome Project. Contact us to discover how BSI can customize products/services to suit your research requirements.
For more detail please visit our About Us
Please Contact Us :
Address: 612 E. Main street
City: Lewisville
State: Texas
Country: USA
Postal Code: 75057
Phone Number: 972-420-8505
Founded in 1984, Bio-Synthesis, Inc. was first known as OCS Laboratories. It was the first producer of commercially available synthetic DNA and, in 1985, became a producer of synthetic peptides. In 1989, OCS incorporated as Bio-Synthesis, Inc. and moved its laboratories to Lewisville, Texas. Today, BSI occupies 10,000 square feet of modern laboratory space (completed in 1995) located 20 miles from downtown Dallas and 10 miles from D/FW airport. Among the surrounding academic institutions are: University of Texas Southwestern Medical School (12 miles), University of North Texas (10 miles), and University of North Texas Health Science Center (25 miles). These universities provide excellent library resources. Since its inception, BSI has steadily expanded its product lines and services to meet the growing needs of the molecular biology community. It has maintained its position as an aggressive, innovative company in a highly competitive marketplace without sacrificing quality. In the beginning, our primary emphasis was on synthesizing high quality DNA primers and linkers, which were the initial uses of oligos. Today, newer technologies, such as gene construction, PCR, mutagenesis, combinatorial libraries, dye/adduct labeling, DNA microarrays, peptide-nucleic acid chimeras, etc. have challenged the molecular biology field. In response, BSI has branched into several related areas including DNA paternity testing, DNA HLA typing, PNA synthesis, genomic sequencing, fluorescence-based genotyping, custom organic synthesis and other molecular biology based applications.
The Research and Development Division comprises a number of Ph.D. and M.D. professionals with backgrounds in molecular biology, immunology, nucleic acids, peptide synthesis, general organic chemistry, and automated amino acid sequencing. The Molecular Biology Division is set up to handle most modern experimental procedures; the Immunology Division specializes in immunodiagnostic-based reagents.
Not only has BSI continued to provide quality DNA products and services for the research community, but it has also become a world leader in providing custom peptide products and services. Using state-of-the-art solid phase peptide chemistries, BSI provides high quality custom peptides, performs carrier conjugations, antipeptide antibody production, antigenic peptide design, synthesis of long and/or modified peptides, MALDI TOF analysis, contract research, consultation services and more.
Biomedical researchers worldwide in universities, biotech companies, private clinics, and government agencies use products from Bio-Synthesis, Inc. in studies ranging from PCR diagnostics to cancer research and the Human Genome Project. Contact us to discover how BSI can customize products/services to suit your research requirements.
For more detail please visit our About Us
Please Contact Us :
Address: 612 E. Main street
City: Lewisville
State: Texas
Country: USA
Postal Code: 75057
Phone Number: 972-420-8505
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BIO-SYNTHESIS, INC., is a leading life science products company with over 20 years of experience in the design and synthesis of Custom Peptide, small molecules and reagents for small scale research and bulk pharmaceutical trials. Using state of the art technology in our well-equipped laboratories.
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BSI is a U.S. based company whose primary emphasis is on the synthesis of high quality custom products for a variety of applications and a full-service contract manufacturing organization (CMO) delivering research, development and production services for cGMP clinical batch manufacturing.
BIO-SYNTHESIS
BIO-SYNTHESIS, INC., is a leading life science products company with over 20 years of experience in the design and synthesis of Custom Peptide, small molecules and reagents for small scale research and bulk pharmaceutical trials. Using state of the art technology in our well-equipped laboratories.
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