Early proteins

The folding of a single polypeptide chain in three-dimensional space is referred to as its tertiary structure. As discussed in Section 6.2, all of the information needed to fold the protein into its native tertiary structure is contained within the primary structure of the peptide chain itself. With this in mind, it was disappointing to the biochemists of the 1950s when the early protein structures did not reveal the governing principles in any particular detail. It soon became apparent that the proteins knew how they were supposed to fold into tertiary... 

Natural proteins have been selected not only to fold into stable structures, but to do so under various conditions and in reasonable time. More obviously, they have been selected for particular functions that often require hydrophobic surface groups and nonregular secondary structures. Finally, most extant proteins have been indirectly selected to be insensitive to most mutations. We note that those early proteins that could not accept numerous mutations without loss of function or structure would not adapt to changing conditions or functional requirements. All of these factors mean that natural proteins are unlikely to fit any single optimization concept. 

Gilead Z, Jeng YH, Wold WS, Sugawara K, Rho HM, Harter ML, Green M. 1976. Immunological identification of two adenovirus 2-induced early proteins possibly involved in cell transformation. Nature 264 263-266. 

Early protein crystallographers, proceeding by analogy with studies of other crystalline substances, examined dried protein crystals and obtained no diffraction patterns. Thus X-ray diffraction did not appear to be a promising tool for analyzing proteins. In 1934, J. D. Bernal and Dorothy Crowfoot (later Hodgkin) measured diffraction from pepsin crystals still in the mother liquor. Bernal and Crowfoot recorded sharp diffraction patterns, with reflections out to distances in reciprocal space that correspond in real space to the distances between atoms. The announcement of their success was, in effect, a birth announcement for protein crystallography. 

Personal reminiscences in macromolecular and protein chemistry have been recorded.205 Both D. E. Koshland206and J. T. Edsall207 have reported their own experiences in early protein research, the former stressing his induced fit theory and the latter describing his long career at Harvard after two years with Hopkins at... 

D. E. Koshland and J. T. Edsall have recorded their own experiences in early protein research. Koshland stresses the value of his induced fit theory,192 while Edsall describes his long career at Harvard after two years with Hopkins at Cambridge.193 Fruton has also described the work of T. B. Osborne (1859-1928), noted for his analyses of amino-acids from seed proteins.194 The idea that enzymes might be proteins was a matter of heated debate among chemists from about 1915, including arguments between Willstatter and James Sumner, who in 1926 isolated the enzyme urease and showed it to be a protein.195 However, while it is most important to emphasize protein chemistry, the contributions made to protein science by physics... 

Zhu ZY, Veldman GM, Cowie A, Carr A, Schaffhausen B, Kamen R (1984), Construction and functional characterization of polyomavirus genomes that separately encode the three early proteins, J. Virol. 51 170-180. 

Fella K, Gluckmann M, Hellmann J, Karas M, Kramer PJ, Kroger M. Use of two-dimensional gel electrophoresis in predictive toxicology Identification of potential early protein biomarkers in chemically induced hepatocarcinogenesis. Proteomics 2005 5(7) 1914-1927. 

Early protein chemical studies, followed by site-directed mutagenesis experiments in E. coli, identified five catalytically important eysteine residues in R1 (Mao et at., 1992a berg et at., 1989 Lin et al., 1987) (ef Figure 2). These cysteines are ... 

High-resolution structures of hundreds of protein molecules are currently available and many more are being determined with increasing rapidity. This pace of structure determination owes as much to other technological advances as it does to the development of molecular biology, which made unlimited quantities of pure proteins available. Early protein structures were determined using weak X-ray sources and manual scanning of X-ray films. Calculations were performed on computers with inadequate power. Thus, many years were required to determine the structure of even small proteins (Branden and Tooze, 1991). 

Samaniego LA, Neiderhiser L, DeLuca NA. 1998. Persistence and expression of the herpes simplex virus genome in the absence of immediate-early proteins. J. Virol. 72 3307-20... 

Temperature-sensitive Mutants - A number of temperature-sensitive mutants of SV40 have been analyzed. Those found defective in the complementation A group and the physical map regions which code for the early proteins (T antigen and t) were also found defective in their ability to transform cells. The temperature-sensitive transformation defect was reversible at permissive temperatures, i.e., transformed colonies appeared. Mutants defective in the formation of late proteins (viral structural proteins) were able to transform cells. Therefore, functional early proteins are required to effect and maintain transformation. The early proteins necessary for transformation also permit viral DNA replication and the stimulation of host cell DNA synthesis. The exact biochemical functions required for transformation have not yet been determined. 

Deletion Mutants - Another approach has been the construction of deletion mutants by the judicious use of restriction enz3mies and appropriate exonucleases. The sites of the deletions were mapped in some Instances they were widely separated but still affected a single protein. The functional ability of the mutants was then determined. The results, while at an early stage, are in agreement with the conclusions reached with the temperature-sensitive mutants. The early proteins must be functional to effect DNA replication, stimulation of host cell DNA synthesis and cell transformation. Interestingly, not all three of the late proteins appear to be required for virus production. Much more will surely come from these studies. 

ALB was one of the first identified biochemical markers of malnutrition and has long been used in population studies. ALB is a relatively insensitive index of early protein malnutrition because there is a large amount normally found in the body (4 to 5 g/kg of body weight), it is highly distributed in the extravascular compartment (60%), and it has a long half-life (18 to 20 days). However, chronic protein deficiency in the setting of adequate nonprotein calorie intake leads to marked hypoalbuminemia because of a net ALB loss from the intravascular and extravascular compartments (kwashiorkor). Serum ALB concentrations also are affected by moderate-to-severe calorie deficiency hepatic, renal, and GI disease and infection, tramna, stress, and burns. In many cases, interpretation of serum ALB concentrations relative to nutrition status is difficult however, a positive correlation between decreased serum ALB concentrations and poor clinical outcome has been demonstrated in a variety of settings. Additionally, serum ALB concentrations of 2.5 g/dL or less can be expected to exacerbate ascites and peripheral, pulmonary, and GI mucosal edema due to decreased colloid oncotic pressure. 

Compression-molded soy protein plastics are rigid and brittle without plasticizers present in the formulation (Paetau et al., 1994). Water absorption of early protein plastics could not be reduced to the very low levels that were obtained with synthetic, petroleum-derived resin products however, color, dyeing, and strength properties were good and production costs were relatively low (Johnson Myers, 1995). 

The mRNA induction of PDGF, bFGF and TGF pi in vascular SMC in vitro and in vivo as a direct consequence of an endothelial lesion or atherosclerotic plaque formation is preceded by the activation of several immediate-early genes [314,315]. In particular, PDGF and TGF pi expression, unlike that of bFGF, is dependent on early protein synthesis [315]. There is compelling evidence that the products of these immediate-early... 

Fomivirsen Fomivirsen is an antisense oligonucleotide that binds to mRNA of CMV, inhibiting early protein synthesis. The drug is injected intravitreally for treatment of CMV retinitis. 

Fomivirsen inhibits CMV by at least two mechanisms. The first is a sequence-specific antisense binding to inhibit expression of immediate-early genes, thus preventing viral replication. The second is sequence-independent and involves inhibition of adsorption of CMV to host cells, probably by direct binding to viral coat proteins (20,21). The reduction of immediate-early protein synthesis occurs in a dose-dependent manner. Although it does inhibit viral replication, fomivirsen does not eradicate the virus whose DNA, as for all herpesviruses, is integrated into the human genome. Therefore, treatment will have to continue for the life of the patient. 

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