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co and post translation modification

The document provides an overview of co- and post-translational modifications in proteins, explaining key processes such as protein folding, cleavage, and the addition of functional groups. It describes specific mechanisms, including chaperone-mediated folding and enzyme-mediated modifications, and outlines the significance of these modifications in terms of protein function and degradation. Additionally, it details the pathways of protein degradation, highlighting the roles of ubiquitin-proteasome and lysosomal proteolysis mechanisms.

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SEMINAR ON CO & POST-TRANSLATIONAL MODIFICATION CO & POST-TRANSLATIONAL MODIFICATION By KAUSHAL KUMAR SAHU Assistant Professor (Ad Hoc) Department of Biotechnology Govt. Digvijay Autonomous P. G. College Raj-Nandgaon ( C. G. )
CONTENTS:  Introduction  Protein modifications  Folding • Chaperon mediated • Enzymatic  Cleavage  Addition of functional groups • Chemical groups • Hydrophobic groups  Proteolysis  Conclusion  Reference Co & Post Translational Modification
INTRODUCTION:  Protein modification can occur at any step in the "life cycle" of a protein. For example, many proteins are modified shortly after translation is completed to mediate proper protein folding or stability or to direct the nascent protein to distinct cellular compartments .  Other modifications occur after folding and localization are completed to activate or inactivate catalytic activity or to otherwise influence the biological activity of the protein. Co & Post Translational Modification
PROTEIN MODIFICATIONS I] Folding:  It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil.  The correct three-dimensional structure is essential to function, although some parts of functional proteins may remain unfolded. A] Chaperone Mediated:  The term `molecular chaperone` appeared first in the literature in 1978, and was invented by Ron Laskey.  There are many different families of chaperones; each family acts to aid protein folding in a different way. Co & Post Translational Modification
Family Size Location Example Hsp 60 ~ 1 MDa Mitochondria, Chloroplast GroEL/GroES in E.coli Hsp 70 ~ 70 kDa Cytoplasm, ER , Mitochondria, Chloroplast DnaK in E.coli Hsp 90 ~ 90 kDa ER, cytosol, mitochondria HtpG in E.coli Hsp 100 ~ 100 kDa Mitochondria, ER chloroplast Clp in E.coli Co & Post Translational Modification
Co & Post Translational Modification Fig: Model of bacterial chaperones involved in protein folding Fig: Model of eukaryotic chaperones involved in protein folding
Co & Post Translational Modification B] Enzyme Mediated : E.g. Prolyl hydroxylase, Peptidyl prolyl isomerase (PPI), PDI Protein Disulphide Isomerases (PDI): Protein disulfide isomerase or PDI is an enzyme in the ER that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold. Fig; PDI contains an active-site with two reduced cysteine sulfhydryl (–SH) groups. The ionized (–S−) form of one of these groups reacts with disulfide (S – S) bonds on nascent or newly completed proteins to form a disulfide-bonded PDI- substrate protein intermediate. This generates a free –S− group on the protein, which, in turn, can react with another disulfide bond in the protein to form a new disulfide bond and another free –S− group. In this way, the disulfide bonds on a protein can rearrange themselves until the most stable conformation for the protein is achieved, and free PDI is released.
II] Cleavage  Cleavage is one of the important step in maturation of many proteins.  Co-Translational Cleavage: It may occur for the removal of signal sequences or for the removal of initiator amino acids. Co & Post Translational Modification Fig: Removal of initiator amino acid in a) Prokaryotes b) Eukaryotes
Post-Translational Cleavage:  Proteolytic trimming: Many proteins ( insulin, collagen) & proteases ( trypsin, chymotrypsin) are initially synthesized as larger inactive precursor proteins which are proteolytically trimmed to produce their active final forms. This process is also called as protein splicing. Co & Post Translational Modification
III] Addition Of Functional Group Co & Post Translational Modification Compartment Modification Nucleus Acetylation(Histone), Phosphorylation Lysosome Mannose 6Phosphate labeled N-linked sugar Mitochondria N-formyl Acylation Chloroplast N-formyl Acylation Golgi body N & O-linked Glycosylation (oligosaccharide),Sulfation, Palmitoylation ER N-linked Glycosylation(oligosaccharide), GPI anchor Cytosol Acetylation, Methylation, Phosphorylation Ribosome Myristoylation Plasma membrane N & O-linked Glycosylation, GPI anchor Extracellular fluid N & O-linked Glycosylation, Acetylation, Phosphorylation, Hydroxylation
a) Chemical groups: Co & Post Translational Modification Chemical groups Amino acid Function 1] Glycosylation arginine, asparagine, cystei ne, hydroxylysine, serine, threonine, tyrosine, or tryptophan Carbohydrates in the form of aspargine-linked (N-linked) or serine/threonine- linked (O-linked) oligosaccharides are major structural components of many cell surface and secreted proteins 2] Phosphorylation serine, threonine, tyrosine (O-linked), or histidine (N-linked) Reversible, regulation of many cellular processes including cell cycle, growth, apoptosis and signal transduction pathways. 3] Methylation Lysine, glutamine etc Methylation is a well-known mechanism of epigenetic regulation, as histone methylation and demethylation
Co & Post Translational Modification Fig: Glycosylation of protein in ER b) Lipidation: Proteins are covalently modified with a variety of lipids, including fatty acids, isoprenoids, and cholesterol. Lipidation is a method to target proteins to membranes in organelles (endoplasmic reticulum [ER], Golgi apparatus, and mitochondria), vesicles (endosomes, lysosomes) and the plasma membrane.
Co & Post Translational Modification Modification Group attached Enzyme involved Significance N Myristoylation: Covalent attachment of myristate to an N- terminal glycine (commonly) Myristate (C14 fatty acid) N-myristoyl -transferase (NMT) Co-translational, irreversible Membrane targeting & signal Transduction. E.g. Src-family kinases, are N-myristoylated. Palmitoylation: thioester linkage of palmitate to cytoplasmic cysteine residues. Palmitate ( C16 Fatty acid) palmitoyl acyl transferases (PATs) Reversible, on/off switch to regulate membrane localization, strengthen other types of lipidation, such as myristoylation or farnesylation
Prenylation: thioether linkage Of an isoprenoidlipid to specific cysteine residues within 5 amino acids from the C-terminus. farnesyl (C15) or geranylgeranyl (C20) farnesyl transferase (FT) or geranylgerany l transferases (GGT I and II) Irreversible, anchor protein to membrane, e.g. all members of the Ras superfamily GPI anchored: linkage of glycosyl- phosphatidylinositol (GPI) to the C- terminus of extracellular proteins glycosyl-phosphatid -ylinositol (a Glycolipid) Reversible, anchors protein to external face of plasma membrane often localized to cholesterol- and sphingolipid- rich lipid rafts, which act as signaling platforms on the plasma membrane. Co & Post Translational Modification
Co & Post Translational Modification Fig; Glycosylphosphatidylinositol (GPI) anchors contain two fatty acid chains, an oligosaccharide portion consisting of inositol and other sugars, and ethanolamine. The GPI anchors are assembled in the ER and added to polypeptides anchored in the membrane by a carboxy-terminal membrane- spanning region. The membrane spanning region is cleaved, and the new carboxy terminus is joined to the NH2 group of ethanolamine immediately after translation is completed, leaving the protein attached to the membrane by the GPI anchor.
IV] Protein Degradation  Levels of protein within cells are determined not only by rates of synthesis but also by rates of degradation.  In eukaryotic cells, two major pathways—the ubiquitin- proteasome pathway and lysosomal proteolysis—mediate protein degradation.  The major pathway of selective protein degradation in eukaryotic cells uses ubiquitin as a marker that targets cytosolic and nuclear proteins by the attachment of ubiquitin to the amino group of the side chain of a lysine residue for rapid proteolysis.  Ubiquitin is a 76-amino-acid polypeptide that is highly conserved in all eukaryotes (yeasts, animals, and plants).  E.g.: 1] Degradation of cyclin B by ubiquitin allowing cell to exit mitosis & enter interphase again.  2] Serves as marker for endocytosis. Co & Post Translational Modification
Co & Post Translational Modification 1] Ubiquitin is activated by being attached to the ubiquitin-activating enzyme, E1. 2] The ubiquitin is then transferred to a second enzyme, called ubiquitin conjugating enzyme (E2) 3] The final transfer of ubiquitin to the target protein is then mediated by a third enzyme, called ubiquitin ligase or E3, which is responsible for the selective recognition of appropriate substrate proteins. Additional ubiquitins are then added to form a multiubiquitin chain. Such polyubiquinated proteins are recognized and degraded by a large, multisubunit protease complex, called the proteasome. Ubiquitin is released in the process, so it can be reused in another cycle. It is noteworthy that both the attachment of ubiquitin and the degradation of marked proteins require energy in the form of ATP.
B] Lysosomal Proteolysis  The other major pathway of protein degradation in eukaryotic cells involves the uptake of proteins by lysosomes.  Lysosomes are membrane- enclosed organelles that contain an array of digestive enzymes, including several proteases. Co & Post Translational Modification
Co & Post Translational Modification Cell & Molecular Biology 5th edition Gerald Karp Molecular Cell Biology 6th edition Harvey Lodish The Cell A Molecular Approach 4th edition Geoffrey M Cooper Internet sources