intro_s1ands2

intro_s1ands2 - Introduction Session 1 and 2 (Ubiquitin,...

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Introduction Session 1 and 2 (Ubiquitin, proteasome and human disease) Appendage of ub prote Figure by MIT OCW. After Goodsell, D.S. The Oncologist 8, 293-294. Courtesy of Sam Griffiths-Jones. Used with permission. Source: "Peptide models for protein beta-sheets." PhD thesis, University of Nottingham, 2001. iquitin monomers to a in substrate. Ubiquitin is a small, 76 aa protein which gets appended to another proteins, as a “label”. The protein substrate has amino groups in the side chains of its Lys aa residues. Ubiquitin has a C-terminal Gly. The carboxyl group of this Gly forms an isopeptide bond with the amino group of the Lys in the protein substrate (see figure). Ubiquitin also has several Lys that can act as internal acceptors for binding to the C-t Gly of new ubiquitin molecules, allowi ng the formation of a chain.
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DISCOVERY OF THE ROLE OF UBIQUITIN N IN PROTEIN DEGRADATION. . HISTORICAL FACTS. . Courtesy of Sam Griffiths-Jones. Used with permission. Source: "Peptide models for protein beta-sheets." PhD thesis, University of Nottingham, 2001. ± (1975) Ubiquitin was first isolated by Gideon Goldstein and colleagues from the thymus (reason why it was originally thought to be a thymic hormone ) . ± But because it was later found in all tissues and eukaryotic organisms it received the name of UBIQUITIN (for ‘ubiquitous’ protein). ± (1977) Harris Goldknopf and Ira Busch found a DNA-associated protein that had one C-t but two N-t! The short arm of this Y- shaped unusual protein was joined through its C-terminal to the ε - amino group of an internal Lys of the histone H2A. ± Margaret Dayhoff soon identified it as Ubiquitin (a protein initially described as free by Goldstein). ± (1969-1971) Avram Hershko studies regulation of tyrosine aminotransferase by its degradation Æ he found that degradation of the enzyme was arrested by inhibitors of cellular energy production (fluoride, azide) That was the first indication that an as-yet-unknown energy- dependent proteolytic system must exist. ± (1971-1980’s) Hershko decided to identify this energy-dependent system responsible for the degradation of proteins, by means of classi cal biochemistry. His aims were: - to reproduce the ATP-dependent protein breakdown in a cell-free system. - to fractionate such system to find the mode of action of its components.
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± (1977) Etlinger and Goldberg discovered an ATP-dependent proteolytic system occurring in reticulocytes (red blood cells). Therefore, Hershko, helped by his grad student Aron ciechanover and Irwin Rose (Fox Chase cancer Center, Philadelphia) decided to isolate the ATP- dependent proteolytic system from these cells. Reticulocyte lysates were fractionated on DEAE-cellulose (anionic exchange chromatography) into two crude fractions: Æ Fxn1(not adsorbed), with most of the hemoglobin .
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This note was uploaded on 11/11/2011 for the course BIO 7.344 taught by Professor Bobsauer during the Spring '08 term at MIT.

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intro_s1ands2 - Introduction Session 1 and 2 (Ubiquitin,...

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